Casp3 encodes rat caspase-3 (CPP32/apopain/Yama), the principal executioner caspase of apoptosis and a member of the peptidase C14A family. It is synthesised as an inactive cytosolic zymogen and is activated by initiator caspases (caspase-8 downstream of death receptors, caspase-9 downstream of the mitochondrial apoptosome) that cleave it at Asp175-Ser176, followed by autocatalytic prodomain removal at Asp28, generating the p17 and p12 subunits that assemble into the active heterotetramer. The active enzyme is a cysteine-type endopeptidase (EC 3.4.22.56) with an absolute requirement for aspartate at P1 and a preference for DEVD-like recognition motifs. Acting mainly in the cytoplasm and cytosol, and on nuclear substrates in dying cells, it carries out the limited, selective proteolysis that constitutes the execution phase of apoptosis: cleavage of PARP, of the ICAD/DFF45 inhibitor to release the nuclease that fragments chromosomal DNA, of cytoskeletal and repair proteins, and of downstream caspases. In rat, caspase-3 is induced and activated in neurons after cerebral ischaemia, seizures, excitotoxic and hypoxic injury, in cardiomyocytes after ischaemia/reperfusion, and in ovarian follicular and luteal cells, and its inhibition by Z-DEVD-FMK is protective. Beyond cell death, sublethal caspase-3 activity contributes to non-apoptotic processes including synapse pruning and synaptic vesicle regulation, keratinocyte and erythroid differentiation, and proliferation of cerebellar granule-cell precursors, and caspase-3 cleavage of gasdermin D links apoptosis to the control of pyroptosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT places cytoplasmic activity at a deep caspase-family node seeded by experimentally characterised caspases across insects, nematodes, fish and mammals (including rat Casp3 itself, RGD:2275). Effector caspases are synthesised as soluble cytoplasmic zymogens and act on cytoplasmic substrates. Reason: The node placement is sound: caspase zymogen storage and activation in the cytoplasm is ancestral to the whole family, and rat Casp3 sits squarely inside the clade. Rat Casp3 also has its own IDA support for cytoplasmic localization (PMID:21630211), so its appearance in the WITH/FROM list is the expected marker of descendant experimental grounding rather than circularity. Supporting Evidence: file:rat/Casp3/Casp3-deep-research-falcon.md Caspase-3 is synthesized as an inactive precursor and activated by proteolytic processing PMID:21630211 cleaved caspase-3 and DNase-1 were found in the epithelial cytoplasms |
| GO:0006915 apoptotic process | IBA GO_REF:0000033 | ACCEPT | Summary: Involvement in the apoptotic process at the pan-caspase node. Apoptotic function is the defining, ancestral role of the caspase family and rat Casp3 is a canonical effector member. Reason: Core assignment. The IBD node is supported by experimental annotations across Drosophila, C. elegans, zebrafish, mouse and rat caspases; there is no evidence of loss or functional divergence in the rat lineage. Supporting Evidence: file:rat/Casp3/Casp3-deep-research-falcon.md apoptotic signaling cascades converge on **caspase-3 activation** as a dominant effector step that drives widespread but selective proteolysis of apoptosis substrates |
| GO:0004197 cysteine-type endopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Cysteine-type endopeptidase activity inherited at the caspase-family node. This is the defining catalytic activity of Casp3 (EC 3.4.22.56), a C14A peptidase that hydrolyses peptide bonds C-terminal to Asp in DEVD-type motifs. Reason: Core molecular function. The catalytic Cys/His dyad and the QACRG active-site motif are retained in rat P55213, and rat caspase-3 DEVDase activity has been measured directly in vivo, so the phylogenetic assertion is corroborated on the target itself. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000047947 · pan-caspase ancestral node SUPPORTS TRANSFER Deep caspase-family IBD seeded by experimentally characterised caspases across insects, nematodes, fish and mammals; rat Casp3 sits inside the clade and retains the full catalytic machinery (see residue claims), so the inherited activity is verified on the target. Supporting Evidence: file:rat/Casp3/Casp3-deep-research-falcon.md the canonical executioner (effector) caspase in apoptosis, functioning as a cysteine protease that cleaves substrates **after Asp residues** file:rat/Casp3/Casp3-deep-research-falcon.md caspase-3 mRNA/protein induction in hippocampus and caudate-putamen after ischemia, increased p17 immunoreactivity over 4-72 h, increased DEVDase activity |
| GO:0006508 proteolysis | IBA GO_REF:0000033 | ACCEPT | Summary: Proteolysis at a caspase-3/-7 effector subnode (PTN008499732). Substrate cleavage is the biological process through which caspase-3 acts. Reason: Core process assignment, correctly placed at the effector-caspase node and directly consistent with rat experimental data showing caspase-3-dependent substrate cleavage. Supporting Evidence: file:rat/Casp3/Casp3-deep-research-falcon.md apoptotic signaling cascades converge on **caspase-3 activation** as a dominant effector step that drives widespread but selective proteolysis of apoptosis substrates |
| GO:0031264 death-inducing signaling complex | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Part_of death-inducing signalling complex, transferred from a subnode seeded by rat Casp3 itself (RGD:2275, from the spinal-cord-injury DISC study). Caspase-3 is co-recruited with Fas, FADD, caspase-8 and cFLIP into raft-associated DISC platforms after injury. Reason: Not wrong: rat caspase-3 has direct IDA evidence for DISC association (PMID:17518537). But DISC membership is a context-specific, extrinsic-pathway recruitment event rather than the constitutive site of effector-caspase action, so it is kept as non-core rather than as a core location. Supporting Evidence: PMID:17518537 Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC) |
| GO:0097194 execution phase of apoptosis | IBA GO_REF:0000033 | ACCEPT | Summary: Execution phase of apoptosis, placed at the effector-caspase node (PTN008499732) with human CASP3 and mouse Casp3 as descendant evidence. Reason: This is the most precise core process term for an executioner caspase: caspase-3 acts downstream of initiator caspases to dismantle the cell. Node placement is appropriate and rat Casp3 is inside the effector clade. Supporting Evidence: file:rat/Casp3/Casp3-deep-research-falcon.md apoptotic signaling cascades converge on **caspase-3 activation** as a dominant effector step that drives widespread but selective proteolysis of apoptosis substrates |
| GO:0008047 enzyme activator activity | IBA GO_REF:0000033 | MODIFY | Summary: Enzyme activator activity at the effector-caspase node. Caspase-3 does activate other proteases (notably caspase-6 and caspase-9) by proteolytic maturation, but 'enzyme activator activity' is an uninformative grandparent term. Reason: The underlying claim is sound but the term is too general for a protease whose activating action is specifically proteolytic maturation of downstream caspases during apoptosis. Replace with the apoptosis-specific caspase-activator term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN008499732 · effector caspase (CASP3/CASP7) ancestral node SUPPORTS TRANSFER effector-caspase node; caspase-3 does proteolytically activate downstream caspases, so the activator claim is inherited correctly, but the term chosen is a generic MF-regulator parent RGD:2275 · rat Casp3 SUPPORTS TRANSFER the target's own experimental annotation is one of the descendant evidences behind this IBD node; expected, not circular Proposed replacements: cysteine-type endopeptidase activator activity involved in apoptotic process Supporting Evidence: file:rat/Casp3/Casp3-deep-research-falcon.md apoptotic signaling cascades converge on **caspase-3 activation** as a dominant effector step that drives widespread but selective proteolysis of apoptosis substrates |
| GO:0043525 positive regulation of neuron apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Positive regulation of neuron apoptotic process at the pan-caspase node, with rat Casp3, Casp2, Casp6, Casp8 and C. elegans CED-3 among descendants. Rat Casp3 has its own IMP support in cortical neurons (PMID:18404518). Reason: Genuine mammalian biology, but this is a cell-type-restricted instance of the core apoptotic execution role rather than a distinct function. Kept as non-core. Supporting Evidence: PMID:18404518 Z-DEVD-FMK, a specific and irreversible cell permeable inhibitor of caspase-3, prevented BzATP-induced apoptosis in rPCNs |
| GO:0030182 neuron differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Neuron differentiation, from a caspase-3/-7 subnode. Non-apoptotic caspase-3 activity in proliferating and differentiating neural precursors is documented in rat cerebellum (PMID:15248196). Reason: Plausible and supported by rat data showing active caspase-3 in EGL cells without apoptotic hallmarks, but this non-apoptotic role is a secondary, context-dependent function rather than the core effector-protease assignment. Supporting Evidence: PMID:15248196 Proliferative (Ki67-positive) and differentiated (TUJ1-positive) cells within the EGL exhibited a cytosolic expression of caspase-3 |
| GO:0030216 keratinocyte differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Keratinocyte differentiation, from a caspase-3/-7 subnode with mouse Casp3 experimental evidence. Caspase-3 contributes to terminal keratinocyte differentiation in mammals. Reason: Plausible mammalian pleiotropy inherited at the correct node, but tissue-restricted and not part of the core effector-caspase function. Kept as non-core, consistent with the ISO row for the same term. |
| GO:0030218 erythrocyte differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Erythrocyte differentiation, from a caspase-3/-7 subnode with human CASP3 evidence. Transient caspase-3 activity is required during erythroid maturation. Reason: Real but lineage-restricted developmental role; kept as non-core, matching the ISO and IEA rows for the same term. |
| GO:0004197 cysteine-type endopeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: UniProt automatic annotation of cysteine-type endopeptidase activity from human and mouse CASP3 orthologs plus caspase InterPro signatures (IPR002398, IPR011600). Reason: Correct and at the right level of specificity; agrees with the IBA, ISS and ISO rows and with the EC 3.4.22.56 assignment for P55213. Supporting Evidence: file:rat/Casp3/Casp3-deep-research-falcon.md the canonical executioner (effector) caspase in apoptosis, functioning as a cysteine protease that cleaves substrates **after Asp residues** |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Automatic cytoplasm localization from ortholog records and the UniProt SL-0086 subcellular location. Reason: Correct core localization for an effector caspase zymogen; consistent with the IBA, ISO and rat IDA rows. Supporting Evidence: PMID:21630211 cleaved caspase-3 and DNase-1 were found in the epithelial cytoplasms |
| GO:0006508 proteolysis | IEA GO_REF:0000120 | ACCEPT | Summary: Automatic proteolysis annotation from ortholog and InterPro peptidase signatures. Reason: Correct core process term for a peptidase; matches the IBA, ISO and IDA rows. |
| GO:0007413 axonal fasciculation | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA rule-based transfer of 'axonal fasciculation' (the bundling of axons into fascicles). No caspase-3 evidence supports a role in axon bundling; the underlying literature concerns caspase-mediated axonal degeneration, a different process. Reason: The rule generalises a neuronal caspase phenotype into a term whose definition (collection of axons into a fascicle) does not match the experiments. Kept only as a flagged over-annotation rather than removed, and aligned with the IMP row for the same term. |
| GO:0008234 cysteine-type peptidase activity | IEA GO_REF:0000120 | MODIFY | Summary: Automatic 'cysteine-type peptidase activity' from mouse Casp3 and InterPro IPR015917. Reason: Not wrong but one level too general: caspase-3 is specifically an endopeptidase. Replace with cysteine-type endopeptidase activity, consistent with the ISO and IDA rows for the same term. Proposed replacements: cysteine-type endopeptidase activity |
| GO:0010212 response to ionizing radiation | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA rule assigning 'response to ionizing radiation'. Caspase-3 is activated downstream of radiation-induced damage but does not sense or mount the response. Reason: Stimulus-response terms of this kind describe the upstream trigger rather than a caspase-3 function; the informative content is already captured by the apoptotic-execution terms. Flagged as over-annotation rather than removed, consistent with the IEP row for response to X-ray. |
| GO:0048513 animal organ development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA rule assigning the very high-level term 'animal organ development'. Reason: Too general to be informative. Caspase-3 does contribute to several developmental programmes, but those are already captured by specific non-core terms (heart development, anterior neural tube closure, keratinocyte/erythrocyte differentiation). |
| GO:0001818 negative regulation of cytokine production | IEA GO_REF:0000107 | REMOVE | Summary: Automatic transfer of 'negative regulation of cytokine production' from human CASP3. Reason: Removed for the same reason as the ISO row for this term: the human source evidence is an indirect, context-specific inflammatory read-out rather than a conserved caspase-3 function, and there is no rat evidence for a dedicated cytokine-regulatory role. |
| GO:0004175 endopeptidase activity | IEA GO_REF:0000107 | MODIFY | Summary: Automatic 'endopeptidase activity' from mouse Casp3. Reason: Correct but too broad; the catalytic mechanism is cysteine-type. Replace with cysteine-type endopeptidase activity, matching the ISO and ISS rows for the same term. Proposed replacements: cysteine-type endopeptidase activity |
| GO:0004190 aspartic-type endopeptidase activity | IEA GO_REF:0000107 | REMOVE | Summary: Automatic 'aspartic-type endopeptidase activity' from mouse Casp3. Reason: Mechanistically wrong: caspase-3 cleaves *after* Asp residues but uses an active-site cysteine nucleophile, not an aspartic-protease mechanism. This is a classic misreading of 'cysteine-aspartate protease'. Consistent with the ISO row, which is also removed. Supporting Evidence: file:rat/Casp3/Casp3-deep-research-falcon.md the canonical executioner (effector) caspase in apoptosis, functioning as a cysteine protease that cleaves substrates **after Asp residues** |
| GO:0004861 cyclin-dependent protein serine/threonine kinase inhibitor activity | IEA GO_REF:0000107 | REMOVE | Summary: Automatic transfer of 'cyclin-dependent protein serine/threonine kinase inhibitor activity' from mouse Casp3. Reason: There is no evidence that caspase-3 is a direct CDK inhibitor; the mouse source evidence is phenotype-based cell-cycle data. Removed, consistent with the ISO row for the same term. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Automatic nuclear localization from human and mouse CASP3 records. Reason: Active caspase-3 does enter the nucleus during apoptosis to cleave nuclear substrates, so this is not wrong, but it is a context-dependent apoptotic localization rather than the default site of action. Aligned with the ISO rows for nucleus. |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Automatic cytosol localization from human CASP3. Reason: Correct core localization: the caspase-3 zymogen is cytosolic and the active heterotetramer acts there. Consistent with the ISO cytosol rows. Supporting Evidence: file:rat/Casp3/Casp3-deep-research-falcon.md Caspase-3 is synthesized as an inactive precursor and activated by proteolytic processing |
| GO:0006915 apoptotic process | IEA GO_REF:0000107 | ACCEPT | Summary: Automatic 'apoptotic process' from human CASP3. Reason: Correct core process; agrees with the IBA and ISO rows. |
| GO:0008233 peptidase activity | IEA GO_REF:0000120 | MODIFY | Summary: Automatic 'peptidase activity' from ARBA and ortholog records. Reason: Correct but two levels too general. Replace with cysteine-type endopeptidase activity, consistent with the ISO rows for the same term. Proposed replacements: cysteine-type endopeptidase activity |
| GO:0008627 intrinsic apoptotic signaling pathway in response to osmotic stress | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Automatic transfer of 'intrinsic apoptotic signalling pathway in response to osmotic stress' from mouse Casp3. Reason: Caspase-3 acts downstream of, and is common to, all intrinsic apoptotic routes; singling out osmotic stress is an over-specific stimulus context. Aligned with the two ISO rows for this term, which are also marked as over-annotated. |
| GO:0014069 postsynaptic density | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Automatic postsynaptic-density localization from mouse Casp3. Reason: Localised caspase-3 activity at synapses is documented in mammalian neurons, but this is a specialised non-apoptotic neuronal context, not a core location. Aligned with the ISO row. |
| GO:0016485 protein processing | IEA GO_REF:0000107 | MODIFY | Summary: Automatic 'protein processing' from human CASP3. Reason: The essence (limited proteolytic cleavage of substrates) is right, but 'protein processing' is a vague catch-all. Replace with proteolysis, consistent with the two ISO rows for this term. Proposed replacements: proteolysis |
| GO:0030163 protein catabolic process | IEA GO_REF:0000107 | MODIFY | Summary: Automatic 'protein catabolic process' from human CASP3. Reason: Caspase-3 performs limited, site-specific cleavage rather than bulk protein degradation, so 'protein catabolic process' mischaracterises the activity. Replace with proteolysis, consistent with the ISO and IDA rows for this term. Proposed replacements: proteolysis |
| GO:0030218 erythrocyte differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Automatic 'erythrocyte differentiation' from human CASP3. Reason: Real but lineage-restricted developmental role; kept as non-core, matching the IBA and ISO rows for the same term. |
| GO:0031647 regulation of protein stability | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Automatic 'regulation of protein stability' from human CASP3. Caspase-3-mediated cleavage of the trafficking adaptor GGA3 stabilises BACE1, and rat data support this (PMID:17553422). Reason: Not a primary function but a demonstrated downstream consequence of substrate cleavage, with direct experimental support in the GGA3/BACE system. Kept as non-core and aligned with the IDA and ISO rows for this term. Supporting Evidence: PMID:17553422 increases in BACE and beta-secretase activity are due to posttranslational stabilization following caspase activation |
| GO:0032880 regulation of protein localization | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Automatic 'regulation of protein localization' from human CASP3. Reason: Any protease that cleaves trafficking adaptors will indirectly alter protein localization; this is a downstream consequence rather than a caspase-3 function, and the term adds no mechanistic information beyond the proteolysis annotations. |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000120 | MODIFY | Summary: ARBA/ortholog transfer of 'positive regulation of apoptotic process'. Reason: Caspase-3 executes rather than regulates apoptosis; the precise term for its role is execution phase of apoptosis. Aligned with the ISO and IMP rows for this term. Proposed replacements: execution phase of apoptosis Supporting Evidence: file:rat/Casp3/Casp3-deep-research-falcon.md apoptotic signaling cascades converge on **caspase-3 activation** as a dominant effector step that drives widespread but selective proteolysis of apoptosis substrates |
| GO:0051604 protein maturation | IEA GO_REF:0000107 | MODIFY | Summary: Automatic 'protein maturation' from human CASP3. Reason: Caspase-3 does mature substrates (e.g. downstream caspases), but the generic 'protein maturation' term understates the catalytic act. Replace with proteolysis, consistent with the ISO row for this term. Proposed replacements: proteolysis |
| GO:0070269 pyroptotic inflammatory response | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Automatic 'pyroptotic inflammatory response' from human CASP3. Reason: Caspase-3 intersects pyroptosis mainly by cleaving and inactivating gasdermin D, i.e. it limits rather than performs pyroptosis, and this is an infection-specific cross-talk context. Aligned with the ISO row for this term. Supporting Evidence: file:rat/Casp3/Casp3-deep-research-falcon.md caspase-3 can cleave **gasdermins** and participate in apoptosis-pyroptosis crosstalk |
| GO:0072734 cellular response to staurosporine | IEA GO_REF:0000107 | REMOVE | Summary: Automatic 'cellular response to staurosporine' from human CASP3. Reason: Staurosporine is a laboratory apoptosis inducer; caspase-3 activation downstream of it is an assay read-out, not a biological response function. Removed, consistent with the ISO row for this term. |
| GO:0097193 intrinsic apoptotic signaling pathway | IEA GO_REF:0000107 | MODIFY | Summary: Automatic 'intrinsic apoptotic signalling pathway' from human CASP3. Reason: Caspase-3 is the convergence point of the intrinsic and extrinsic pathways rather than a component specific to the intrinsic branch. Replace with execution phase of apoptosis, consistent with the ISO row for this term. Proposed replacements: execution phase of apoptosis |
| GO:0097194 execution phase of apoptosis | IEA GO_REF:0000107 | ACCEPT | Summary: Automatic 'execution phase of apoptosis' from human CASP3. Reason: Correct core process term for an executioner caspase; agrees with the IBA and ISO rows. Supporting Evidence: file:rat/Casp3/Casp3-deep-research-falcon.md apoptotic signaling cascades converge on **caspase-3 activation** as a dominant effector step that drives widespread but selective proteolysis of apoptosis substrates |
| GO:0098693 regulation of synaptic vesicle cycle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Automatic 'regulation of synaptic vesicle cycle' from mouse Casp3. Reason: Specialised non-apoptotic neuronal role with mouse experimental support; kept as non-core, aligned with the ISO row. |
| GO:0098883 synapse pruning | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Automatic 'synapse pruning' from mouse Casp3. Reason: Local, sublethal caspase-3 activity in synapse elimination is well documented in mammalian neurons but is a specialised context; kept as non-core, aligned with the ISS and ISO rows. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Automatic 'glutamatergic synapse' localization from mouse Casp3. Reason: Plausible neuronal context of action rather than a core location; aligned with the ISO row. |
| GO:0140639 positive regulation of pyroptotic inflammatory response | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Automatic 'positive regulation of pyroptotic inflammatory response' from human CASP3. Reason: The direction is questionable as well as over-specific: the best-characterised caspase-3 effect on gasdermin D is inactivating cleavage that limits pyroptosis. Aligned with the ISO row for this term. Supporting Evidence: file:rat/Casp3/Casp3-deep-research-falcon.md caspase-3 can cleave **gasdermins** and participate in apoptosis-pyroptosis crosstalk |
| GO:1902004 positive regulation of amyloid-beta formation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Automatic 'positive regulation of amyloid-beta formation' from human CASP3, matching the rat IDA evidence that caspase cleavage of GGA3 stabilises BACE1 and raises Abeta (PMID:17553422). Reason: A demonstrated but disease-context downstream consequence of caspase-3 substrate cleavage, not a core function. Kept as non-core and aligned with the IDA and ISO rows for this term. Supporting Evidence: PMID:17553422 increases in BACE and beta-secretase activity are due to posttranslational stabilization following caspase activation |
| GO:0098883 synapse pruning | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity transfer of synapse pruning from mouse Casp3. Reason: Same judgement as the IEA and ISO rows for this term: a genuine but specialised neuronal remodelling role, kept as non-core. |
| GO:0098883 synapse pruning | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3, where synapse pruning has direct experimental support. This mammalian neuronal remodeling role is plausible in rat but is context-specific and not part of Casp3 core apoptotic function. |
| GO:0045471 response to ethanol | IEP PMID:30926569 Effect of saffron (stigma of Crocus sativus L.) aqueous extr... | MARK AS OVER ANNOTATED | Summary: IEP from a saffron/ethanol toxicity study in Wistar rats, in which ethanol raised caspase-3 (together with Bax/Bcl2 and caspases-8 and -9) in kidney and liver. Reason: Classic expression-response over-annotation: caspase-3 protein rises because ethanol triggers apoptosis, which caspase-3 then executes. Correlated expression does not make caspase-3 part of an ethanol-response programme, and the informative content is already covered by the apoptotic-execution terms. Supporting Evidence: PMID:30926569 ethanol increased the expression of Bax/Bcl2 ratio, caspase-3, -8, and -9 |
| GO:0045471 response to ethanol | IEP PMID:23102656 Effect of repetitive daily ethanol intoxication on adult rat... | MARK AS OVER ANNOTATED | Summary: IEP from a repetitive ethanol-intoxication study of adult rat hippocampus and entorhinal cortex. Total caspase-3 was elevated, but the authors explicitly report that cleaved (active) caspase-3 was undetectable and that the degeneration was non-apoptotic (parthanatos-like). Reason: Even weaker than the usual IEP case: the paper reports negligible caspase-3 activation, so an ethanol-response role for caspase-3 is not supported. Marked as over-annotated rather than removed, matching the other response-to-ethanol row. Supporting Evidence: PMID:23102656 the robust PARP-1 elevations accompanied by negligible caspase-3 |
| GO:0036269 swimming behavior | IEP PMID:33574912 Insulin-like growth factor-1 improves postoperative cognitiv... | MARK AS OVER ANNOTATED | Summary: The cited study uses the Morris Water Maze (a swimming-based test) to assess learning and memory in a postoperative-cognitive-dysfunction model, and measures caspase-3 by Western blot purely as a hippocampal apoptosis marker. Swimming is the assay modality, not a function of caspase-3, which is an apoptotic executioner protease. Reason: Spurious IEP over-annotation derived from the swimming-based Morris Water Maze memory assay; the paper assays cognition/apoptosis, not swimming behaviour, and caspase-3 has no proximal role in locomotion or swimming. Supporting Evidence: PMID:33574912 To assess learning and memory abilities, MWM tests were performed as described previously |
| GO:0043523 regulation of neuron apoptotic process | IEP PMID:33574912 Insulin-like growth factor-1 improves postoperative cognitiv... | MARK AS OVER ANNOTATED | Summary: IEP from a postoperative-cognitive-dysfunction model in aged rats, where hippocampal caspase-3 protein rose after splenectomy and fell with IGF-1 treatment, in parallel with TUNEL-positive neurons. Reason: Caspase-3 here is a read-out of neuronal apoptosis, not a demonstrated regulator of it. Where caspase-3 does have a neuronal-apoptosis annotation it is the more specific GO:0043525 supported by inhibitor-based IMP evidence (PMID:18404518); this broader 'regulation of' term added on expression correlation is an over-annotation. Supporting Evidence: PMID:33574912 the levels of APP, BACE-1, Aβ, caspase3 and Bax were increased following splenectomy |
| GO:1990418 response to insulin-like growth factor stimulus | IEP PMID:33574912 Insulin-like growth factor-1 improves postoperative cognitiv... | MARK AS OVER ANNOTATED | Summary: IEP derived from the same study, in which exogenous IGF-1 administration lowered hippocampal caspase-3 levels. Reason: A pharmacological intervention that reduces apoptosis will reduce caspase-3 activation; this does not place caspase-3 in an IGF-1 response pathway. Classic stimulus-response over-annotation from expression data. Supporting Evidence: PMID:33574912 the levels of APP, BACE-1, Aβ, caspase3 and Bax were increased following splenectomy |
| GO:0043065 positive regulation of apoptotic process | ISO GO_REF:0000121 | MODIFY | Summary: Transferred from mature human CASP3 chain annotations, but the GO term is broader than the conserved effector step. The more precise conserved transfer is execution phase of apoptosis. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION GRANULARITY MISMATCH Sources checked: UniProtKB:P42574 · human CASP3 SUPPORTS TRANSFER ortholog record supports pro-apoptotic function; the effector caspase executes rather than regulates apoptosis, so the term rather than the transfer is wrong UniProtKB:P42574-PRO_0000004571 · human CASP3 subunit p17 SUPPORTS TRANSFER ortholog record supports pro-apoptotic function; the effector caspase executes rather than regulates apoptosis, so the term rather than the transfer is wrong UniProtKB:P42574-PRO_0000004572 · human CASP3 subunit p12 SUPPORTS TRANSFER ortholog record supports pro-apoptotic function; the effector caspase executes rather than regulates apoptosis, so the term rather than the transfer is wrong Proposed replacements: execution phase of apoptosis |
| GO:1902512 positive regulation of apoptotic DNA fragmentation | ISO GO_REF:0000121 | ACCEPT | Summary: Transferred from mature human CASP3 chain annotations. Promotion of apoptotic DNA fragmentation is a canonical downstream consequence of effector caspase-3 activation and is conserved across mammals. |
| GO:0005737 cytoplasm | IDA PMID:21630211 Immunohistochemical study of the apoptosis process in epider... | ACCEPT | Summary: IDA: immunohistochemistry of rat palm/foot-pad epidermis localised cleaved (active) caspase-3 to the cytoplasm of stratum spinosum to stratum granulosum keratinocytes under physiological conditions. Reason: Direct rat evidence for the core cytoplasmic localization of active caspase-3; consistent with the IBA, IEA and ISO cytoplasm rows. Supporting Evidence: PMID:21630211 cleaved caspase-3 and DNase-1 were found in the epithelial cytoplasms |
| GO:0072347 response to anesthetic | IEP PMID:27498600 Neuroprotective effects of caffeic acid phenethyl ester agai... | MARK AS OVER ANNOTATED | Summary: IEP from a study of sevoflurane-induced neurodegeneration in neonatal rats, where cleaved caspase-3 was measured by immunohistochemistry and western blot as an apoptosis marker. Reason: Anaesthetic exposure induces neuronal apoptosis, which caspase-3 executes; the anaesthetic is the stimulus, not a substrate or partner of caspase-3. Expression/activation correlation does not justify a 'response to anesthetic' process annotation. Supporting Evidence: PMID:27498600 the expression of cleaved caspase‑3 was analyzed by immunohistochemistry |
| GO:0014069 postsynaptic density | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3, where postsynaptic-density localization has direct synaptic evidence. This neuronal localization is plausible in rat but is a specialized non-core context rather than the principal Casp3 function. |
| GO:0098693 regulation of synaptic vesicle cycle | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3 with direct synaptic evidence. Regulation of synaptic vesicle cycle reflects a specialized neuronal remodeling role, not the core conserved apoptotic assignment for rat Casp3. |
| GO:0098978 glutamatergic synapse | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3 with direct synaptic evidence at glutamatergic synapses. Likely a real mammalian neuronal context, but not a core rat Casp3 function. |
| GO:0016485 protein processing | ISO GO_REF:0000121 | MODIFY | Summary: Transferred from human CASP3, where the source evidence reflects protease-mediated substrate cleavage. Protein processing is too generic; proteolysis is the clearer conserved process term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P42574 · human CASP3 SUPPORTS TRANSFER source annotation itself is sound; only the GO term granularity is at issue for the rat transfer Proposed replacements: proteolysis |
| GO:0001818 negative regulation of cytokine production | ISO GO_REF:0000121 | REMOVE | Summary: Transferred from human CASP3, but the source support is an indirect cross-taxonomic evidence chain rather than a clean human ortholog experiment. This is too far from rat Casp3 core function and is likely an over-transfer. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH ROLE CONFLATION Sources checked: UniProtKB:P42574 · human CASP3 SUPPORTS SOURCE BUT NOT TARGET immune-context human evidence; caspase-3 effects on cytokine output are indirect consequences of killing or of gasdermin cleavage, not a cytokine-regulatory function that should transfer to rat |
| GO:0001666 response to hypoxia | IEP PMID:24089674 Neuroprotective effects of microRNA-210 on hypoxic-ischemic ... | MARK AS OVER ANNOTATED | Summary: IEP from a neonatal hypoxic-ischaemic encephalopathy model, where miR-210 reduced neuronal apoptosis and caspase activity. Reason: Caspase-3 activation is the downstream execution step after hypoxic injury, not a hypoxia sensing or response function. Aligned with the other response-to-hypoxia IEP row. Supporting Evidence: PMID:24089674 suppressed neuronal apoptosis by inhibiting caspase activity and regulating the balance between bcl-2 and bax levels |
| GO:0006915 apoptotic process | ISO GO_REF:0000121 | ACCEPT | Summary: Transferred from human CASP3, which has strong experimental support for apoptotic process. This is a core, conserved effector-caspase assignment for rat Casp3. |
| GO:0070269 pyroptotic inflammatory response | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Transferred from human CASP3 with direct source evidence, but pyroptotic inflammatory response is a specialized context-dependent cross-talk role rather than a broadly conserved core rat Casp3 function. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P42574 · human CASP3 SUPPORTS TRANSFER human CASP3 does intersect pyroptosis by cleaving gasdermin D, but this is an infection/inflammasome-specific cross-talk context rather than a general rat function |
| GO:0005829 cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: Transferred from human CASP3 with direct localization evidence. Cytosolic localization is consistent with conserved effector-caspase biology in rat. |
| GO:0051604 protein maturation | ISO GO_REF:0000121 | MODIFY | Summary: Transferred from human CASP3, but protein maturation is too generic for an effector caspase that primarily acts through substrate proteolysis. Use proteolysis instead. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P42574 · human CASP3 SUPPORTS TRANSFER source annotation itself is sound; only the GO term granularity is at issue for the rat transfer Proposed replacements: proteolysis |
| GO:0140639 positive regulation of pyroptotic inflammatory response | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Transferred from human CASP3 with direct source evidence, but positive regulation of pyroptotic inflammatory response is a specialized context and too specific for a general rat orthology transfer. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: CONTEXT OR TISSUE MISMATCH REGULATORY SIGN INVERSION Sources checked: UniProtKB:P42574 · human CASP3 SUPPORTS TRANSFER the best-characterised human caspase-3 effect on gasdermin D is inactivating cleavage that limits pyroptosis, so a positive-regulation term may also have the sign wrong |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | ACCEPT | Summary: Transferred from human CASP3 with direct localization evidence. Cytoplasmic localization is a conserved and appropriate core assignment for rat Casp3. |
| GO:0097193 intrinsic apoptotic signaling pathway | ISO GO_REF:0000121 | MODIFY | Summary: Transferred from human CASP3, but the intrinsic-pathway label is too pathway-specific for a downstream effector caspase that operates in multiple apoptotic routes. The more precise conserved transfer is execution phase of apoptosis. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P42574 · human CASP3 SUPPORTS TRANSFER human CASP3 acts downstream of both intrinsic and extrinsic routes; restricting the rat transfer to the intrinsic branch overstates specificity Proposed replacements: execution phase of apoptosis |
| GO:0005634 nucleus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from human CASP3 with direct source evidence for nuclear activity/localization in apoptotic settings. This is a valid context-dependent localization but not a core rat Casp3 assignment. |
| GO:0030163 protein catabolic process | ISO GO_REF:0000121 | MODIFY | Summary: Transferred from human CASP3, but protein catabolic process overgeneralizes the substrate-cleavage role. Proteolysis is the clearer conserved process term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P42574 · human CASP3 SUPPORTS TRANSFER source annotation itself is sound; only the GO term granularity is at issue for the rat transfer Proposed replacements: proteolysis |
| GO:0097194 execution phase of apoptosis | ISO GO_REF:0000121 | ACCEPT | Summary: Transferred from mouse Casp3, where execution phase of apoptosis is directly supported. This is a core, conserved effector-caspase role in rat. |
| GO:0010996 response to auditory stimulus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from chinchilla Casp3, where the source ortholog has direct experimental evidence for auditory-response biology. The term may reflect a genuine mammalian sensory context, but it is non-core for rat Casp3. |
| GO:0004197 cysteine-type endopeptidase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of cysteine-type endopeptidase activity from human CASP3. Reason: Correct core molecular function; rat P55213 retains the C14A catalytic dyad and DEVDase activity has been measured directly in rat tissue. Supporting Evidence: file:rat/Casp3/Casp3-deep-research-falcon.md caspase-3 mRNA/protein induction in hippocampus and caudate-putamen after ischemia, increased p17 immunoreactivity over 4-72 h, increased DEVDase activity |
| GO:0004175 endopeptidase activity | ISS GO_REF:0000024 | MODIFY | Summary: Sequence-similarity transfer of 'endopeptidase activity' from mouse Casp3. Reason: Correct but unnecessarily broad given that the catalytic mechanism is known. Replace with cysteine-type endopeptidase activity, consistent with the ISO and IEA rows for this term. Proposed replacements: cysteine-type endopeptidase activity |
| GO:0004175 endopeptidase activity | ISO GO_REF:0000121 | MODIFY | Summary: Transferred from mouse Casp3 with direct catalytic evidence, but endopeptidase activity is too broad. The conserved specific activity is cysteine-type endopeptidase activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:107739 · mouse Casp3 SUPPORTS TRANSFER ortholog catalytic evidence is sound; the transferred term is a parent of the specific cysteine-type endopeptidase activity Proposed replacements: cysteine-type endopeptidase activity |
| GO:0006508 proteolysis | ISO GO_REF:0000121 | ACCEPT | Summary: Transferred from human CASP3 with direct source evidence. Proteolysis is a core conserved biological process for rat Casp3. |
| GO:0006508 proteolysis | IDA PMID:17553422 Depletion of GGA3 stabilizes BACE and enhances beta-secretas... | ACCEPT | Summary: IDA: caspase activation during cerebral ischaemia leads to cleavage of the trafficking adaptor GGA3, with consequent post-translational stabilisation of BACE1. Reason: Direct experimental support for caspase-3-mediated proteolysis of a defined substrate; a core process assignment consistent with the IBA, IEA and ISO proteolysis rows. Supporting Evidence: PMID:17553422 increases in BACE and beta-secretase activity are due to posttranslational stabilization following caspase activation |
| GO:0031647 regulation of protein stability | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from human CASP3. Caspase-3-mediated cleavage of substrates such as the trafficking adaptor GGA3 alters the stability of downstream proteins. Reason: Realigned from REMOVE to KEEP_AS_NON_CORE because rat Casp3 has its own direct experimental evidence for this effect (PMID:17553422, IDA). It is a substrate-specific downstream consequence rather than a core function, so non-core is the right status. |
| GO:0031647 regulation of protein stability | IDA PMID:17553422 Depletion of GGA3 stabilizes BACE and enhances beta-secretas... | KEEP AS NON CORE | Summary: IDA: caspase-mediated cleavage of GGA3 stabilises BACE1, increasing beta-secretase activity. Reason: A real, directly demonstrated consequence of caspase-3 substrate cleavage, but it is a substrate-specific downstream effect rather than a core function. Kept as non-core; the ISO row for this term has been aligned to the same action. Supporting Evidence: PMID:17553422 increases in BACE and beta-secretase activity are due to posttranslational stabilization following caspase activation |
| GO:1902004 positive regulation of amyloid-beta formation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from human CASP3. Caspase-dependent GGA3 cleavage stabilises BACE1 and raises amyloid-beta production. Reason: Realigned from REMOVE to KEEP_AS_NON_CORE because the same mechanism has direct rat experimental support (PMID:17553422, IDA). Disease-context and substrate-specific, hence non-core rather than removed. |
| GO:1902004 positive regulation of amyloid-beta formation | IDA PMID:17553422 Depletion of GGA3 stabilizes BACE and enhances beta-secretas... | KEEP AS NON CORE | Summary: IDA: caspase-dependent GGA3 depletion raises BACE1 and Abeta levels, linking caspase-3 activity to amyloid-beta production after ischaemia. Reason: Experimentally grounded but disease-context and substrate-specific; kept as non-core rather than removed, and the ISO row for this term has been aligned to the same action. Supporting Evidence: PMID:17553422 increases in BACE and beta-secretase activity are due to posttranslational stabilization following caspase activation |
| GO:0051146 striated muscle cell differentiation | IEP PMID:28899909 Depletion of the mRNA translation initiation inhibitor, prog... | MARK AS OVER ANNOTATED | Summary: IEP from L6 myotube-formation experiments in which PDCD4 knockdown impaired myotube formation and reduced PARP, caspase-7 and caspase-3 cleavage. Reason: Caspase-3 was measured as an apoptosis read-out in a study about PDCD4; the correlation between reduced caspase-3 cleavage and impaired differentiation does not establish that caspase-3 drives striated muscle cell differentiation in rat. Supporting Evidence: PMID:28899909 Analysis of poly (ADP-ribose) Polymerase (PARP), caspase 7 and caspase 3 indicated reduced apoptosis in PDCD4-deficient cells |
| GO:0071887 leukocyte apoptotic process | IEP PMID:26861981 Time course of apoptosis induced by photodynamic therapy wit... | KEEP AS NON CORE | Summary: IEP from photodynamic therapy of the rat LT12 acute myeloid leukaemia line, where cleaved caspase-3 peaked at 6-12 h during the apoptotic window. Reason: This is a cell-type-specific instance of the core apoptotic execution role (apoptosis of a leukocyte-lineage cell) rather than a separate function, and the evidence is treatment-induced expression of the cleaved protein. Kept as non-core. Supporting Evidence: PMID:26861981 cleaved caspase-3 delayed to 6-12 h |
| GO:0001554 luteolysis | IEP PMID:25332219 Endoplasmic reticulum stress-mediated apoptotic pathway is i... | KEEP AS NON CORE | Summary: IEP from rat corpus luteum regression, where caspase-3 transcript and protein rose with ER-stress markers during late-luteal stage in parallel with TUNEL-positive luteal cells. Reason: Luteolysis proceeds largely by apoptosis of luteal cells, so caspase-3 involvement is biologically reasonable, but this is a tissue-specific instance of the core apoptotic role supported only by expression correlation. Kept as non-core. Supporting Evidence: PMID:25332219 the expression levels of CHOP, caspase 12, and caspase 3 were increased during the process of CL regression |
| GO:0007413 axonal fasciculation | IMP PMID:25898930 Death Receptor 6 and Caspase-6 Regulate Prion Peptide-Induce... | MARK AS OVER ANNOTATED | Summary: IMP from prion-peptide-induced axonal degeneration in rat spinal neurons. DR6 knockdown blocked activation of both caspase-6 and caspase-3 and prevented degeneration, but the authors report cleaved caspase-3 confined to cell bodies while cleaved caspase-6 is present in axons, and axonal protection was achieved with caspase-6 inhibition. Reason: GO:0007413 is defined as the collection of axons into a fascicle, which is not the process assayed; the paper concerns axonal degeneration and places caspase-6, not caspase-3, in the axonal compartment. We have only the abstract, so the annotation is flagged as an over-annotation rather than removed, and the IEA row for the same term is aligned. Supporting Evidence: PMID:25898930 cleaved caspase-3 is only enriched in cell bodies, but cleaved caspase-6 is expressed in both cell bodies and axons |
| GO:0043025 neuronal cell body | IDA PMID:25898930 Death Receptor 6 and Caspase-6 Regulate Prion Peptide-Induce... | KEEP AS NON CORE | Summary: IDA: cleaved caspase-3 immunoreactivity was specifically enriched in the cell bodies of rat spinal neurons after prion-peptide treatment. Reason: Well-supported cell-type-specific localization that refines where active caspase-3 acts in neurons, but the core locations remain cytoplasm/cytosol. Kept as non-core. Supporting Evidence: PMID:25898930 cleaved caspase-3 is only enriched in cell bodies, but cleaved caspase-6 is expressed in both cell bodies and axons |
| GO:0061713 anterior neural tube closure | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3 with direct developmental phenotype evidence. This may be a real mammalian developmental context, but it is pleiotropic and non-core for rat Casp3. |
| GO:0004197 cysteine-type endopeptidase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Second sequence-similarity transfer of cysteine-type endopeptidase activity from human CASP3 (duplicate of the other ISS row). Reason: Duplicate rows for the defining molecular function are unproblematic; accepted as core. Supporting Evidence: file:rat/Casp3/Casp3-deep-research-falcon.md the canonical executioner (effector) caspase in apoptosis, functioning as a cysteine protease that cleaves substrates **after Asp residues** |
| GO:0004197 cysteine-type endopeptidase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Transferred from human CASP3 with extensive direct catalytic evidence. This is the defining conserved molecular function of rat Casp3. |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | ACCEPT | Summary: Transferred from dog CASP3. Cytoplasmic localization of caspase-3 is conserved and is also supported in rat by direct immunohistochemistry (PMID:21630211). Reason: Aligned with the human- and mouse-sourced cytoplasm rows: although this second-hop transfer is redundant, the localization claim it makes is correct, so accepting it is preferable to removing a true annotation. |
| GO:0008627 intrinsic apoptotic signaling pathway in response to osmotic stress | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Transferred from mouse Casp3 with direct source evidence, but the osmotic-stress variant is too stimulus-specific to treat as a general conserved rat orthology transfer. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: MGI:MGI:107739 · mouse Casp3 SUPPORTS TRANSFER mouse source evidence is for a single stimulus context; caspase-3 executes apoptosis downstream of many stresses and is not osmotic-stress specific |
| GO:0008627 intrinsic apoptotic signaling pathway in response to osmotic stress | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Transferred from dog CASP3. The osmotic-stress-specific intrinsic apoptotic pathway term is an over-specific stimulus context for a downstream effector caspase. Reason: Aligned with the mouse-sourced row for the same term: flagged as an over-annotation rather than removed, since caspase-3 does execute osmotically triggered apoptosis but is not specific to that stimulus. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: RGD:12072547 · dog CASP3 SUPPORTS TRANSFER dog transfer of the same over-specific stimulus term; adds no independent information beyond the mouse-sourced row, which carries the same judgement |
| GO:0043065 positive regulation of apoptotic process | ISO GO_REF:0000121 | MODIFY | Summary: Transferred from mouse Casp3, but positive regulation of apoptotic process is broader than the conserved downstream effector role. Execution phase of apoptosis is the more precise conserved term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION GRANULARITY MISMATCH Sources checked: MGI:MGI:107739 · mouse Casp3 SUPPORTS TRANSFER ortholog record supports pro-apoptotic function; the effector caspase executes rather than regulates apoptosis, so the term rather than the transfer is wrong Proposed replacements: execution phase of apoptosis |
| GO:0043065 positive regulation of apoptotic process | ISO GO_REF:0000121 | MODIFY | Summary: Transferred from dog CASP3. As for the human- and mouse-sourced rows for this term, positive regulation of apoptotic process is broader than the conserved effector role. Reason: Aligned with the other GO:0043065 rows: caspase-3 executes rather than regulates apoptosis, so execution phase of apoptosis is the precise conserved term. The dog transfer adds no independent information but the underlying claim is not wrong, so it is modified rather than removed. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION GRANULARITY MISMATCH Sources checked: RGD:12072547 · dog CASP3 SUPPORTS TRANSFER ortholog record supports pro-apoptotic function; the effector caspase executes rather than regulates apoptosis, so the term rather than the transfer is wrong Proposed replacements: execution phase of apoptosis |
| GO:0072734 cellular response to staurosporine | ISO GO_REF:0000121 | REMOVE | Summary: Transferred from human CASP3, but cellular response to staurosporine is a pharmacologic stimulus-specific context and not an appropriate conserved core orthology transfer. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P42574 · human CASP3 SUPPORTS SOURCE BUT NOT TARGET staurosporine is a laboratory apoptosis inducer; caspase-3 activation in that assay is a read-out, so the term should not propagate as a rat biological process |
| GO:0005634 nucleus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from pig CASP3. Nuclear localization of active caspase-3 occurs in apoptotic cells, where it cleaves nuclear substrates. Reason: Aligned with the other nucleus rows: this is a genuine context-dependent apoptotic localization rather than a default state, so it is kept as non-core rather than removed. |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | ACCEPT | Summary: Transferred from pig CASP3. Cytoplasmic localization is conserved across mammalian caspase-3 orthologs and is directly supported in rat. Reason: Aligned with the other cytoplasm rows for the same reason as the dog-sourced transfer: redundancy is not grounds for removal when the annotation is correct. |
| GO:0005737 cytoplasm | ISO GO_REF:0000121 | ACCEPT | Summary: Transferred from mouse Casp3 with direct localization evidence. Cytoplasmic localization is conserved and appropriate for rat Casp3. |
| GO:0048011 neurotrophin TRK receptor signaling pathway | ISO GO_REF:0000121 | REMOVE | Summary: Transferred from human CASP3, but the source paper treats caspase-3 largely as a downstream apoptosis readout in neurotrophin signaling rather than a dedicated TRK-pathway component. This is an over-transfer. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P42574 · human CASP3 SUPPORTS SOURCE BUT NOT TARGET caspase-3 is a downstream apoptotic read-out of neurotrophin withdrawal rather than a component of TRK receptor signalling |
| GO:0006915 apoptotic process | ISO GO_REF:0000121 | ACCEPT | Summary: Transferred from mouse Casp3 with direct apoptosis evidence, using the acts_upstream_of_or_within qualifier. Reason: Aligned with the other apoptotic-process rows, which are accepted as core. The weaker qualifier is a curation detail rather than a reason to discard a correct, well-supported core assignment; rat Casp3 is directly involved in apoptosis. |
| GO:0005634 nucleus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3 with direct localization evidence. Nuclear localization occurs in apoptotic contexts but is not a core default state for rat Casp3. |
| GO:0002020 protease binding | IPI PMID:17518537 FasL, Fas, and death-inducing signaling complex (DISC) prote... | ACCEPT | Summary: IPI with rat Casp8 (RGD:620945): after spinal cord injury, caspase-3 is co-recruited with caspase-8 into raft-associated DISC platforms, where caspase-8 activates caspase-3. Reason: An informative binding term (protease binding, not bare 'protein binding') with a named, mechanistically meaningful partner: caspase-8 is the initiator protease that directly cleaves and activates caspase-3. Supporting Evidence: PMID:17518537 The formation of the DISC signaling platform leads to rapid activation of initiator caspase-8 and effector caspase-3 |
| GO:0005123 death receptor binding | IPI PMID:17518537 FasL, Fas, and death-inducing signaling complex (DISC) prote... | MARK AS OVER ANNOTATED | Summary: IPI with rat Fas (RGD:619831) from the same spinal-cord-injury DISC study. Reason: The reported evidence is co-immunoprecipitation of caspase-3 with a Fas-nucleated multiprotein DISC that also contains FADD, caspase-8 and cFLIP, i.e. complex co-membership rather than demonstrated direct binding of caspase-3 to the death receptor. The complex association is already captured by the DISC (GO:0031264) annotation, so a direct death-receptor binding molecular function is an over-interpretation. Supporting Evidence: PMID:17518537 Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC) |
| GO:0031264 death-inducing signaling complex | IDA PMID:17518537 FasL, Fas, and death-inducing signaling complex (DISC) prote... | KEEP AS NON CORE | Summary: IDA: after moderate cervical spinal cord injury in rat, caspase-3 is found within the membrane-raft Fas/FADD/caspase-8/cFLIP death-inducing signalling complex. Reason: Directly demonstrated in rat, but DISC recruitment is an extrinsic-pathway, injury-specific context rather than the constitutive site of effector-caspase action. Kept as non-core and aligned with the IBA row for this term. Supporting Evidence: PMID:17518537 Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC) |
| GO:0044877 protein-containing complex binding | IPI PMID:17518537 FasL, Fas, and death-inducing signaling complex (DISC) prote... | MARK AS OVER ANNOTATED | Summary: IPI with Fas and Casp8 recorded as 'protein-containing complex binding' from the same DISC study. Reason: An uninformative binding term that duplicates better-typed annotations from the same experiment: part_of death-inducing signalling complex (GO:0031264, IDA) and protease binding with caspase-8 (GO:0002020, IPI). Retained but flagged as redundant over-annotation. Supporting Evidence: PMID:17518537 Fas associates with the adaptor proteins Fas-associated death domain (FADD), caspase-8, cellular FLIP long form (cFLIPL ), and caspase-3, forming a death-inducing signaling complex (DISC) |
| GO:0004190 aspartic-type endopeptidase activity | ISO GO_REF:0000121 | REMOVE | Summary: Transferred from mouse Casp3, but CASP3 is a cysteine protease, not an aspartic protease. This conflicts with conserved catalytic mechanism and should be removed. Propagation Review Root cause: SOURCE BAD Sources checked: MGI:MGI:107739 · mouse Casp3 SOURCE BAD the transferred molecular function contradicts the caspase catalytic mechanism: caspase-3 cleaves after aspartate but uses an active-site cysteine nucleophile (peptidase family C14A), so an aspartic-protease term is wrong at source |
| GO:0030218 erythrocyte differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from human CASP3 with direct source evidence for erythroid differentiation. This is plausible mammalian pleiotropy, but it is non-core for rat Casp3. |
| GO:0097194 execution phase of apoptosis | ISO GO_REF:0000121 | ACCEPT | Summary: Transferred from human CASP3 with direct source evidence. Execution phase of apoptosis is a core conserved effector-caspase assignment for rat Casp3. |
| GO:0097194 execution phase of apoptosis | ISO GO_REF:0000121 | ACCEPT | Summary: Transferred from mouse Casp3 with direct source evidence, using the acts_upstream_of_or_within qualifier. Reason: Aligned with the other execution-phase rows, which are accepted as core. The qualifier difference does not warrant discarding a correct core assignment. |
| GO:0034349 glial cell apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3 with experimental glial-apoptosis evidence. Likely a real mammalian neural context, but it is non-core for rat Casp3. |
| GO:0051402 neuron apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3 with direct neuronal-apoptosis evidence. This is a plausible mammalian context-specific role, but not a core rat Casp3 assignment. |
| GO:0005634 nucleus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from human CASP3 with direct source evidence for nuclear localization in apoptotic settings. Keep as a non-core context-dependent localization. |
| GO:0004197 cysteine-type endopeptidase activity | ISO GO_REF:0000121 | ACCEPT | Summary: Transferred from mouse Casp3 with extensive direct catalytic evidence. This is a core conserved molecular function for rat Casp3. |
| GO:0009611 response to wounding | ISO GO_REF:0000121 | REMOVE | Summary: Transferred from mouse Casp3 in a wound-response context. This is too context-specific and indirect to retain as a conserved rat orthology transfer. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: MGI:MGI:107739 · mouse Casp3 SUPPORTS SOURCE BUT NOT TARGET mouse wound-healing phenotype places caspase-3 downstream of injury-induced apoptosis; the stimulus context does not transfer as a rat process assignment |
| GO:0016485 protein processing | ISO GO_REF:0000121 | MODIFY | Summary: Transferred from mouse Casp3 with source evidence for substrate cleavage, but protein processing is too generic. Proteolysis is the more appropriate conserved process term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:107739 · mouse Casp3 SUPPORTS TRANSFER source annotation itself is sound; only the GO term granularity is at issue for the rat transfer Proposed replacements: proteolysis |
| GO:0005515 protein binding | IPI PMID:18485100 Nuclear translocation of X-linked inhibitor of apoptosis (XI... | MODIFY | Summary: IPI with rat Xiap (RGD:620692): after neonatal hypoxia-ischaemia, XIAP co-immunoprecipitates with caspase-3, and this association falls as XAF1 sequesters XIAP, releasing caspase-3 activity. Reason: 'Protein binding' is uninformative and should not be retained as-is. The interactor is XIAP, the RING-domain E3 ubiquitin-protein ligase that binds and inhibits caspase-3, so the informative replacement is ubiquitin protein ligase binding, which names the class of partner and preserves the curator's IPI evidence. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:18485100 XIAP co-immunoprecipitated > 9-fold XAF1 protein concurrent with decreased association with caspases 9 and 3 |
| GO:0008234 cysteine-type peptidase activity | IDA PMID:16336964 In vivo delivery of a XIAP (BIR3-RING) fusion protein contai... | MODIFY | Summary: IDA: kainate-induced seizures activated caspase-3 in rat hippocampal CA3, and a PTD-XIAP(BIR3-RING) fusion protein attenuated the activated caspase-3 signal. Reason: The assay reports caspase-3 catalytic activity, so the annotation is sound, but 'cysteine-type peptidase activity' is one level too general for an endopeptidase. Replace with cysteine-type endopeptidase activity, consistent with the other rows for this term. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: PMID:16336964 PTD-XIAP fusion protein attenuated activated caspase-3 and -9 |
| GO:0008234 cysteine-type peptidase activity | IDA PMID:17182030 Inhibition of HtrA2/Omi ameliorates heart dysfunction follow... | MODIFY | Summary: IDA: in rat heart ischaemia/reperfusion in vivo, the HtrA2/Omi inhibitor UCF-101 reduced processing of caspases-9, -3 and -7 alongside preserved XIAP. Reason: Direct evidence of caspase-3 proteolytic processing/activity in rat myocardium; the term is correct but too general. Replace with cysteine-type endopeptidase activity, consistent with the other rows for this term. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: PMID:17182030 inhibition of Caspase-9, Caspase-3, and Caspase-7 processing |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:17869439 Role of inhibitor of apoptosis protein in gentamicin-induced... | MODIFY | Summary: IMP from gentamicin ototoxicity in rat organ-of-Corti explants: XIAP inhibitors increased caspase-3 activation and hair-cell loss, and a caspase-3 inhibitor reduced both. Reason: The experiment establishes that caspase-3 activity drives hair-cell apoptosis, but caspase-3 is the executioner rather than a regulator of the decision to die. Replace with execution phase of apoptosis, consistent with the ISO and IEA rows for this term. Proposed replacements: execution phase of apoptosis Supporting Evidence: PMID:17869439 a caspase-3 inhibitor decreased caspase-3 activation and hair cell loss induced by gentamicin |
| GO:0008234 cysteine-type peptidase activity | IDA PMID:18316105 Implication of caspases and subcellular compartments in tert... | MODIFY | Summary: IDA from compartment-resolved caspase assays in rat hepatocytes exposed to tert-butylhydroperoxide. Caspase-3 enzymatic activity was measured directly, although in this particular model the authors report that caspase-3 was not activated. Reason: The curator's evidence is a direct caspase-3 activity measurement, so the molecular-function assignment stands, but the term should be the specific endopeptidase term. Note that this reference is weak support for caspase-3 activity as such, since the reported result is absence of activation; the catalytic identity rests on the many other direct rat measurements. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: PMID:18316105 The caspase-9 substrates, caspase-3 and caspase-7, were not activated |
| GO:0030163 protein catabolic process | IDA PMID:18316105 Implication of caspases and subcellular compartments in tert... | MODIFY | Summary: IDA of caspase-mediated substrate cleavage in t-BHP-treated rat hepatocytes, recorded as 'protein catabolic process'. Reason: Caspase-3 performs limited, site-specific cleavage rather than bulk protein degradation. Replace with proteolysis, consistent with the ISO, IEA and other IDA rows for this term. Proposed replacements: proteolysis Supporting Evidence: PMID:18316105 The caspase-9 substrates, caspase-3 and caspase-7, were not activated |
| GO:0034349 glial cell apoptotic process | IEP PMID:18931364 Bax and Bid act in synergy to bring about T11TS-mediated gli... | KEEP AS NON CORE | Summary: IEP from T11TS-induced glioma apoptosis, where active caspase-9 and active caspase-3 were detected in glioma cells together with cytochrome c and Apaf-1. Reason: Apoptosis of glial-lineage tumour cells is an instance of the core apoptotic execution role in a particular cell type rather than a separate function. Kept as non-core, aligned with the ISO row for this term. Supporting Evidence: PMID:18931364 the presence of active caspase-9 and active caspase-3 in all the T11TS-treated tumor-bearing groups |
| GO:0035094 response to nicotine | IEP PMID:18477628 Nicotine suppresses tunicamycin-induced, but not thapsigargi... | MARK AS OVER ANNOTATED | Summary: IEP from PC12 cells in which nicotine protected against tunicamycin-induced ER-stress apoptosis; the reported caspase effect in the abstract is on caspase-12, with caspase-3 used as part of the apoptotic read-out. Reason: Nicotine is an exogenous pharmacological stimulus and caspase-3 changes here are a consequence of altered ER-stress apoptosis. Correlated expression does not support a 'response to nicotine' function for the effector protease. Supporting Evidence: PMID:18477628 nicotine reduced the activation of caspase-12 in Tm-treated cells, but not in Tg-treated cells |
| GO:0009749 response to glucose | IDA PMID:19356108 Heme oxygenase-derived carbon monoxide restores vascular fun... | MARK AS OVER ANNOTATED | Summary: IDA from a streptozotocin diabetes / heme-oxygenase study in which adiponectin reduced TNF-alpha-induced caspase-3 activity in endothelial cells. Reason: The measured variable is caspase-3 activity in a diabetic vascular model; glucose is a disease context rather than a stimulus to which caspase-3 mounts a response. The informative content (caspase-3 endopeptidase activity in apoptosis) is captured elsewhere. Supporting Evidence: PMID:19356108 decrease in TNF-alpha-induced ICAM-1 and VCAM-1 and caspase 3 activity in endothelial cells |
| GO:0032025 response to cobalt ion | IEP PMID:18598848 Estradiol protects PC12 cells against CoCl2-induced apoptosi... | MARK AS OVER ANNOTATED | Summary: IEP from PC12 cells where CoCl2 (a chemical hypoxia mimetic) activated the caspase-8/-9/-3 cascade and estradiol limited it. Reason: Cobalt is used here as an experimental hypoxia mimetic; caspase-3 activation is the downstream execution of the induced apoptosis, not a cobalt-response function. Supporting Evidence: PMID:18598848 limited the activities of the caspase cascades, such as caspase-8, -9 and -3 |
| GO:0032355 response to estradiol | IEP PMID:18598848 Estradiol protects PC12 cells against CoCl2-induced apoptosi... | MARK AS OVER ANNOTATED | Summary: IEP from the same study, based on estradiol pre-treatment lowering caspase-3 activity in CoCl2-treated PC12 cells. Reason: A protective hormone treatment that reduces apoptosis will reduce caspase-3 activation; this does not place caspase-3 in an estradiol-response pathway. Supporting Evidence: PMID:18598848 limited the activities of the caspase cascades, such as caspase-8, -9 and -3 |
| GO:0008234 cysteine-type peptidase activity | ISO GO_REF:0000121 | MODIFY | Summary: Transferred from mouse Casp3 with direct catalytic evidence, but cysteine-type peptidase activity is broader than the best conserved term. Use cysteine-type endopeptidase activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:107739 · mouse Casp3 SUPPORTS TRANSFER ortholog catalytic evidence is sound; the transferred term is a parent of the specific cysteine-type endopeptidase activity Proposed replacements: cysteine-type endopeptidase activity |
| GO:0008234 cysteine-type peptidase activity | IDA PMID:17218406 Luteinizing hormone-induced caspase activation in rat preovu... | MODIFY | Summary: IDA: LH and FSH enhanced caspase-3 and -7 activity in theca-interstitial cells of cultured rat preovulatory follicles, and this activation was coupled to P450scc-dependent mitochondrial steroidogenesis and ROS. Reason: Direct measurement of rat caspase-3 catalytic activity in a physiological tissue context; the term is correct but too general. Replace with cysteine-type endopeptidase activity, consistent with the other rows for this term. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: PMID:17218406 LH and FSH enhance caspase-3 and -7 activity and apoptosis in the theca-interstitial cells of rat preovulatory follicles in culture |
| GO:0008233 peptidase activity | ISO GO_REF:0000121 | MODIFY | Summary: Transferred from human CASP3 with direct catalytic support, but peptidase activity is too generic. Use cysteine-type endopeptidase activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P42574 · human CASP3 SUPPORTS TRANSFER ortholog catalytic evidence is sound; the transferred term is a parent of the specific cysteine-type endopeptidase activity Proposed replacements: cysteine-type endopeptidase activity |
| GO:0005829 cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: Transferred from human CASP3 with direct localization evidence. Cytosolic localization is conserved and appropriate for rat Casp3. |
| GO:0001666 response to hypoxia | IEP PMID:18466900 Chronic hypobaric hypoxia induced apoptosis in CA1 region of... | MARK AS OVER ANNOTATED | Summary: IEP from chronic hypobaric hypoxia in rat hippocampus, where active caspase-3 expression and caspase activity rose with TUNEL-positive CA1 cells and p75NTR upregulation. Reason: Caspase-3 executes the apoptosis triggered by hypoxic stress; it is not a hypoxia sensor or a component of a hypoxia-response programme. Aligned with the other response-to-hypoxia IEP row. Supporting Evidence: PMID:18466900 estimation of caspase activity and expression of active Caspase 3 |
| GO:0007611 learning or memory | IMP PMID:18239768 Central injection of caspase inhibitors facilitates the form... | KEEP AS NON CORE | Summary: IMP: intracerebroventricular administration of the caspase-3 inhibitor z-DEVD-fmk (and the pancaspase inhibitor z-VAD-fmk) selectively facilitated formation of conditioned freezing behaviour in rats without affecting consolidation or retrieval. Reason: A genuine inhibitor-based behavioural phenotype implicating caspase activity in memory formation, but z-DEVD-fmk is not fully caspase-3 selective and the role is a specialised non-apoptotic neuronal one. Kept as non-core rather than accepted as a core function. Supporting Evidence: PMID:18239768 The inhibitors selectively facilitated the formation of freezing behavior |
| GO:0009410 response to xenobiotic stimulus | IEP PMID:18274634 The protecting effects and mechanisms of Baicalin and Octreo... | MARK AS OVER ANNOTATED | Summary: IEP from severe acute pancreatitis rats treated with Baicalin or Octreotide, where cardiac Caspase-3 protein expression differed between treatment groups. Reason: Caspase-3 levels track the extent of drug-modulated myocardial apoptosis. 'Response to xenobiotic stimulus' from such treatment-associated expression changes is a classic IEP over-annotation. Supporting Evidence: PMID:18274634 The changes of NF-kappaB, P-Selectin, Bax, Bcl-2, and Caspase-3 protein expression levels in all groups were different |
| GO:0010038 response to metal ion | IEP PMID:18483861 Pravastatin attenuates carboplatin-induced cardiotoxicity vi... | MARK AS OVER ANNOTATED | Summary: IEP from carboplatin cardiotoxicity, where carboplatin raised caspase-3, caspase-9 and cytochrome c in cultured rat cardiomyocytes and pravastatin attenuated this. Reason: The 'metal ion' here is a platinum chemotherapeutic; caspase-3 activation is the execution step of the induced apoptosis, not a metal-response function. Supporting Evidence: PMID:18483861 caused marked apoptosis and increased caspase-3, -9, and cytochrome C |
| GO:0010165 response to X-ray | IEP PMID:18239382 Low-dose local kidney irradiation inhibits progression of ex... | MARK AS OVER ANNOTATED | Summary: IEP from low-dose kidney irradiation in experimental crescentic nephritis, where active caspase-3 and caspase-7 increased in irradiated kidneys alongside p53 and TUNEL-positive cells. Reason: Radiation-induced apoptosis is executed by caspase-3; increased active-caspase-3 staining after irradiation is a downstream marker rather than evidence of an X-ray-response function. Consistent with the ARBA response-to-ionizing-radiation row. Supporting Evidence: PMID:18239382 Western blot analysis showed marked increase in active caspase 3 and active caspase 7 expression in irradiated kidneys |
| GO:0021766 hippocampus development | IEP PMID:18459132 Different expression of caspase-3 in rat hippocampal subregi... | MARK AS OVER ANNOTATED | Summary: IEP describing the spatiotemporal expression profile of active and precursor caspase-3 across rat hippocampal CA1, CA3 and dentate gyrus during postnatal development. Reason: This is a pure expression-pattern study: developmental regulation of caspase-3 levels does not demonstrate that caspase-3 is required for hippocampus development. Any genuine developmental contribution is better captured by the non-core apoptosis and neuron-differentiation terms. Supporting Evidence: PMID:18459132 The expression of active caspase-3 reached a peak at P7 in CA1, at P2 in CA3, and then decreased with age |
| GO:0032496 response to lipopolysaccharide | IEP PMID:18289516 Caspase activation in fetal rat brain following experimental... | MARK AS OVER ANNOTATED | Summary: IEP from intrauterine LPS administration to pregnant rats, where activated caspase-3 appeared in fetal brain 24 h after LPS along with DISC assembly and caspase-8/-9/-10 activation. Reason: LPS triggers inflammation-driven apoptosis that caspase-3 executes; the caspase is not part of an LPS-sensing or LPS-response module. Stimulus-response over-annotation. Supporting Evidence: PMID:18289516 The presence of the activated form of the effector caspase (caspase-3) was observed 24 h after LPS administration |
| GO:0042542 response to hydrogen peroxide | IDA PMID:18479463 Leptin protects H9c2 rat cardiomyocytes from H2O2-induced ap... | MARK AS OVER ANNOTATED | Summary: IDA: leptin pretreatment prevented H2O2-induced increases in caspase-3 cleavage and activity in H9c2 rat cardiomyocytes. Reason: Although the caspase-3 activity measurement is direct, the biological claim is only that oxidative stress triggers apoptosis which caspase-3 executes. 'Response to hydrogen peroxide' as an involved_in process for the effector caspase is an over-annotation of a stimulus context. Supporting Evidence: PMID:18479463 leptin prevented H(2)O(2)-induced increases in caspase-3 cleavage and activity |
| GO:0043200 response to amino acid | IEP PMID:18423997 Glutamate-induced losses of oligodendrocytes and neurons and... | MARK AS OVER ANNOTATED | Summary: IEP from glutamate infusion into rat spinal cord, where nuclei of many cells stained for activated caspase-3 during oligodendrocyte and neuron loss. Reason: Glutamate excitotoxicity is the stimulus; caspase-3 activation is the downstream execution read-out. The authors themselves note that caspase-3 staining persisted for a week without corresponding cell loss, further weakening any direct process claim. Supporting Evidence: PMID:18423997 The nuclei of many cells strongly and specifically stained for activated caspase-3, an indicator of apoptosis, in response to exposure to glutamate |
| GO:0043525 positive regulation of neuron apoptotic process | IMP PMID:18404518 P2X(7) nucleotide receptors mediate caspase-8/9/3-dependent ... | KEEP AS NON CORE | Summary: IMP: in rat primary cortical neurons, P2X7 receptor activation by BzATP caused caspase-3 activation and DNA fragmentation, and the caspase-3 inhibitor Z-DEVD-FMK prevented the apoptosis. Reason: Strong rat inhibitor-based evidence that caspase-3 activity is required for neuronal apoptosis, but this is a cell-type-restricted manifestation of the core apoptotic execution role. Kept as non-core, aligned with the IBA row for this term. Supporting Evidence: PMID:18404518 Z-DEVD-FMK, a specific and irreversible cell permeable inhibitor of caspase-3, prevented BzATP-induced apoptosis in rPCNs |
| GO:0051384 response to glucocorticoid | IEP PMID:18288275 Protecting effects of dexamethasone on thymus of rats with s... | MARK AS OVER ANNOTATED | Summary: IEP from dexamethasone treatment of rats with severe acute pancreatitis, where thymic Caspase-3 protein expression and apoptotic index were higher in the treated group. Reason: Glucocorticoid-induced thymocyte apoptosis is executed by caspase-3; the correlation of caspase-3 protein with steroid treatment does not make caspase-3 part of a glucocorticoid-response pathway. Supporting Evidence: PMID:18288275 The treated group in Caspase-3 protein expression of thymus significantly exceeded the model group at 12 hours |
| GO:0006974 DNA damage response | ISO GO_REF:0000121 | REMOVE | Summary: Transferred from mouse Casp3 in DNA-damage response experiments, but this reflects an upstream stimulus context rather than a core conserved Casp3 function in rat. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:107739 · mouse Casp3 SUPPORTS SOURCE BUT NOT TARGET caspase-3 acts downstream of the DNA damage response as the executioner of the resulting apoptosis; annotating it within the damage-response machinery conflates effector with sensor/transducer |
| GO:0030163 protein catabolic process | IDA PMID:15004018 Minocycline up-regulates Bcl-2 and protects against cell dea... | MODIFY | Summary: IDA from minocycline protection of kidney epithelial cells, where caspase activity was measured across hypoxia, azide, cisplatin and staurosporine challenges. Reason: Caspase-3 acts by limited, site-specific cleavage of substrates rather than bulk protein degradation. Replace with proteolysis, consistent with the ISO, IEA and other IDA rows for this term. Proposed replacements: proteolysis Supporting Evidence: PMID:15004018 Minocycline protected kidney epithelial cells against apoptosis induced by hypoxia, azide, cisplatin, and staurosporine |
| GO:0007605 sensory perception of sound | ISO GO_REF:0000121 | REMOVE | Summary: Transferred from mouse Casp3 as a sensory/hearing phenotype. This is too phenotype-specific for a general conserved rat Casp3 transfer and is weaker than the chinchilla auditory-response row. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: MGI:MGI:107739 · mouse Casp3 SUPPORTS SOURCE BUT NOT TARGET mouse hearing phenotype reflects hair-cell loss by apoptosis, not participation in sound perception itself; the rat auditory context is already covered by the chinchilla-sourced response-to-auditory-stimulus row kept as non-core |
| GO:0007507 heart development | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3 with developmental phenotype evidence. Heart-development effects are plausible pleiotropy but non-core for rat Casp3. |
| GO:0009411 response to UV | ISO GO_REF:0000121 | REMOVE | Summary: Transferred from mouse Casp3 in a UV-response context. This stimulus-specific response is too indirect and over-transferred for rat Casp3. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: MGI:MGI:107739 · mouse Casp3 SUPPORTS SOURCE BUT NOT TARGET UV is an apoptosis-inducing stimulus upstream of caspase-3; the stimulus context does not transfer as a rat process assignment |
| GO:0008233 peptidase activity | ISO GO_REF:0000121 | MODIFY | Summary: Transferred from mouse Casp3 with direct catalytic evidence, but peptidase activity is too generic. Use cysteine-type endopeptidase activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:107739 · mouse Casp3 SUPPORTS TRANSFER ortholog catalytic evidence is sound; the transferred term is a parent of the specific cysteine-type endopeptidase activity Proposed replacements: cysteine-type endopeptidase activity |
| GO:0030182 neuron differentiation | IEP PMID:15248196 Active caspase-3 expression during postnatal development of ... | KEEP AS NON CORE | Summary: IEP: active caspase-3 is expressed in proliferating (Ki67+) and differentiating (TUJ1+) cells of the postnatal rat cerebellar external granule cell layer in the explicit absence of apoptotic hallmarks (no chromatin condensation, no PS externalisation, no TUNEL). Reason: One of the better non-apoptotic caspase-3 datasets in rat: it argues for a role in EGL proliferation/differentiation rather than death. Still a specialised, secondary function supported by expression data, so kept as non-core and aligned with the IBA row for this term. Supporting Evidence: PMID:15248196 Proliferative (Ki67-positive) and differentiated (TUJ1-positive) cells within the EGL exhibited a cytosolic expression of caspase-3 |
| GO:0016005 phospholipase A2 activator activity | IMP PMID:12492473 Signaling events mediating activation of brain ethanolamine ... | MARK AS OVER ANNOTATED | Summary: IMP based on Ac-DEVD-CMK inhibition placing caspase-3 upstream of ceramide-induced activation of a plasmalogen-selective phospholipase A2 in brain. Reason: The experiment is inhibitor-based epistasis: it orders caspase-3 upstream of PLA2 activation but does not show caspase-3 binding or directly activating a phospholipase A2. A dedicated 'phospholipase A2 activator activity' molecular function overstates this; any real effect would most plausibly be indirect or via substrate cleavage, already covered by the proteolysis annotations. Supporting Evidence: PMID:12492473 experiments with Ac-DEVD-CMK (caspase-3 specific inhibitor) have led us to conclude that caspase-3 is downstream of ceramide in activating the brain plasmalogen-selective phospholipase A2 |
| GO:0035556 intracellular signal transduction | IMP PMID:12492473 Signaling events mediating activation of brain ethanolamine ... | MARK AS OVER ANNOTATED | Summary: IMP from the same ceramide/PLA2 study, recorded as the very general term 'intracellular signal transduction'. Reason: Too general to be informative for an effector protease, and derived from the same inhibitor-based epistasis experiment. Retained but flagged as an uninformative over-annotation. Supporting Evidence: PMID:12492473 experiments with Ac-DEVD-CMK (caspase-3 specific inhibitor) have led us to conclude that caspase-3 is downstream of ceramide in activating the brain plasmalogen-selective phospholipase A2 |
| GO:0030216 keratinocyte differentiation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3 with keratinocyte-differentiation phenotype evidence. This is plausible mammalian pleiotropy but non-core for rat Casp3. |
| GO:0045165 cell fate commitment | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3 with developmental phenotype evidence. Cell-fate commitment is non-core pleiotropy rather than a defining rat Casp3 function. |
| GO:0001782 B cell homeostasis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3 knockout immunophenotypes. The biology may be real in lymphocyte contexts, but it is not a core rat Casp3 function. |
| GO:0004861 cyclin-dependent protein serine/threonine kinase inhibitor activity | ISO GO_REF:0000121 | REMOVE | Summary: Transferred from mouse Casp3, but the source evidence is phenotype-based and does not demonstrate a direct cyclin-dependent kinase inhibitor molecular function for CASP3. This is an over-annotation. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:107739 · mouse Casp3 SUPPORTS SOURCE BUT NOT TARGET no established direct cyclin-dependent kinase inhibitor activity for caspase-3; any cell-cycle effect would be an indirect consequence of substrate cleavage, so this should not transfer as a molecular function |
| GO:0030889 negative regulation of B cell proliferation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3 knockout immunophenotypes. Keep only as non-core pleiotropy. |
| GO:0043029 T cell homeostasis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3 knockout immunophenotypes. Keep as non-core because it reflects context-specific immune phenotypes rather than Casp3 core function. |
| GO:0045736 negative regulation of cyclin-dependent protein serine/threonine kinase activity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3 knockout immunophenotypes. The regulatory phenotype may be real, but it is not a core rat Casp3 function. |
| GO:0045786 negative regulation of cell cycle | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3 knockout immunophenotypes. Keep only as non-core pleiotropy. |
| GO:0046007 negative regulation of activated T cell proliferation | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Transferred from mouse Casp3 knockout immunophenotypes. This is a context-specific immune phenotype, not a core rat Casp3 function. |
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