Casp9 encodes caspase-9, the CARD-containing initiator caspase of the intrinsic (mitochondrial) apoptotic pathway. After mitochondrial release of cytochrome c, Apaf-1 oligomerizes into the cytosolic apoptosome and recruits procaspase-9 through CARD-CARD interaction; caspase-9 is activated on this platform and, as a cysteine-type endopeptidase cleaving after aspartate, processes and activates the executioner procaspases-3 and -7. Its activity is also regulated by phosphorylation (an ABL1 site is conserved in rat) and by IAP proteins such as XIAP. Rat studies show caspase-9 activation and a requirement for its activity in intrinsic apoptosis of cardiac endothelial cells after ischemia, of hepatocytes under oxidative stress and of neurons after seizures.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001666 response to hypoxia | IEP PMID:24089674 Neuroprotective effects of microRNA-210 on hypoxic-ischemic ... | MARK AS OVER ANNOTATED | Summary: Caspase-9 protein levels change in neonatal rat brain after hypoxia-ischemia; an apoptosis read-out, not a role in the hypoxia response. Reason: The cited rat study measures caspase-9 protein, cleavage or LEHD-substrate activity as a read-out of intrinsic apoptosis in this experimental model. That shows caspase-9 is activated when cells die under the condition, not that caspase-9 performs any step of the organism's response to the stimulus; its own activity is the apoptotic cascade. The row is a context annotation of the apoptotic role, so it is marked as an over-annotation rather than removed. Full text read: caspase-9 was one of the apoptosis markers blotted to assess miR-210 effects. Supporting Evidence: PMID:24089674 Western blot analysis demonstrated that caspase-3, caspase-9, and bax protein levels were enhanced in miR-210 block rats |
| GO:0001822 kidney development | IEP PMID:27665619 Expression of Cyt-c-Mediated Mitochondrial Apoptosis-Related... | MARK AS OVER ANNOTATED | Summary: Cleaved caspase-9 expression peaks in early postnatal rat proximal tubules; developmental expression pattern, not a developmental function. Reason: Expression of cleaved caspase-9 during renal development (abstract only) is an expression pattern. Caspase-9 executes apoptosis in developing tubules, but kidney development is not a process caspase-9 carries out; its contribution is the general apoptotic cascade already captured by GO:0097193. Supporting Evidence: PMID:27665619 Apaf-1 and cleaved caspase-9 protein expression gradually increased during the embryonic period and peaked during the early postnatal period |
| GO:0002931 response to ischemia | IEP PMID:11934844 Different signaling pathways induce apoptosis in endothelial... | MARK AS OVER ANNOTATED | Summary: Caspase-9 is cleaved in endothelial cells of ischemic rat heart and its inhibitor prevents endothelial apoptosis; context for intrinsic apoptosis. Reason: The cited rat study measures caspase-9 protein, cleavage or LEHD-substrate activity as a read-out of intrinsic apoptosis in this experimental model. That shows caspase-9 is activated when cells die under the condition, not that caspase-9 performs any step of the organism's response to the stimulus; its own activity is the apoptotic cascade. The row is a context annotation of the apoptotic role, so it is marked as an over-annotation rather than removed. Here the inhibitor data (abstract) also show that caspase-9 is needed for ischemia-induced endothelial apoptosis, which is captured by the intrinsic apoptotic signaling pathway rows. Supporting Evidence: PMID:11934844 cleavage of caspase-9 was observed primarily in endothelial cells PMID:11934844 Addition of a specific caspase-9 inhibitor to the perfusate before ischemia prevented endothelial apoptosis |
| GO:0004197 cysteine-type endopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core catalytic activity of caspase-9, the initiator caspase of the apoptosome; IBA from the caspase clade is sound. Reason: Caspase-9 is a CASc-domain peptidase C14A protein with the conserved catalytic His/Cys dyad (rat His275/Cys325). Its endopeptidase activity on procaspase-3 and -7 is established for the mammalian orthologs, and the PAINT node covering the caspases places this activity at the family level; the rat protein retains the catalytic residues, so the inheritance holds. Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 file:rat/Casp9/Casp9-bioinformatics/RESULTS.md Catalytic dyad conserved: human His237 maps to rat His275 and human Cys287 maps to rat Cys325 file:rat/Casp9/Casp9-uniprot.txt Belongs to the peptidase C14A family. |
| GO:0004197 cysteine-type endopeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic mapping of cysteine-type endopeptidase activity from the caspase domain and orthologs; correct core activity. Reason: Same claim as the IBA row; family membership and conservation of the catalytic dyad support it. Supporting Evidence: file:rat/Casp9/Casp9-uniprot.txt Belongs to the peptidase C14A family. file:rat/Casp9/Casp9-bioinformatics/RESULTS.md Catalytic dyad conserved: human His237 maps to rat His275 and human Cys287 maps to rat Cys325 |
| GO:0004197 cysteine-type endopeptidase activity | ISO GO_REF:0000121 | ACCEPT | Summary: ISO transfer of cysteine-type endopeptidase activity from mouse Casp9; correct. Reason: Mouse Casp9 is required for cytochrome c-mediated caspase-3 cleavage, and the rat ortholog retains the catalytic dyad. Supporting Evidence: PMID:9708735 Casp9 is a critical upstream activator of the caspase cascade in vivo file:rat/Casp9/Casp9-bioinformatics/RESULTS.md Catalytic dyad conserved: human His237 maps to rat His275 and human Cys287 maps to rat Cys325 |
| GO:0004197 cysteine-type endopeptidase activity | ISO GO_REF:0000121 | ACCEPT | Summary: ISO transfer of cysteine-type endopeptidase activity from human CASP9; correct. Reason: Human caspase-9 directly cleaves procaspase-3 and procaspase-7 on the apoptosome; the rat ortholog retains the catalytic dyad. Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 PMID:16352606 the latter complex directly cleaves/activates procaspase-7 file:rat/Casp9/Casp9-bioinformatics/RESULTS.md Catalytic dyad conserved: human His237 maps to rat His275 and human Cys287 maps to rat Cys325 |
| GO:0005634 nucleus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Nuclear location transferred from mouse; rat hepatocyte data also show processed caspase-9 moving to the nucleus. Non-core. Reason: Caspase-9 acts in the cytosolic apoptosome. A nuclear pool has been reported, including in rat hepatocytes treated with t-BHP where cleaved caspase-9 and its activity were found in the nucleus, but this is a secondary location of the activated enzyme. Supporting Evidence: PMID:18316105 Procaspase-9 underwent cleavage in mitochondria and translocation to the nucleus, where increased caspase-9 activity was detected |
| GO:0005634 nucleus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO nuclear location from mouse Casp9; plausible secondary location of activated caspase-9. Reason: As for the IEA row: the nuclear pool is supported in rat hepatocytes but is peripheral to the apoptosome function. Supporting Evidence: PMID:18316105 Procaspase-9 underwent cleavage in mitochondria and translocation to the nucleus, where increased caspase-9 activity was detected |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Caspase-9 is a cytoplasmic protein; the caspase-family IBA for cytoplasm is sound and accepted, with cytosol captured by its own rows. Reason: The PAINT node spans the caspase family, whose members act in the cytoplasm, and rat Casp9 itself (cytoplasm IDA by immunohistochemistry) appears among the descendant evidence, which is expected. Cytoplasm is as precise as this family-level inference and the rat immunohistochemistry allow; the more specific cytosol location of the apoptosome is accepted separately on the cytosol rows, so both are kept. Supporting Evidence: PMID:12782307 caspase-9 is in the cytoplasm of non-apoptotic pituitary cells PMID:21630211 Bid, Apaf-1 and cleaved caspase-9 were restricted in the SG |
| GO:0005737 cytoplasm | IDA PMID:21630211 Immunohistochemical study of the apoptosis process in epider... | ACCEPT | Summary: Immunohistochemistry shows cleaved caspase-9 in the cytoplasm of rat epidermal granular-layer cells; accepted at the resolution of the assay. Reason: Immunohistochemical staining cannot separate cytosol from other cytoplasmic compartments, so cytoplasm is as precise as this assay allows (abstract only; cleaved caspase-9 is described in the cytoplasmic staining pattern of the stratum granulosum). The more specific cytosol location is supported by other rows. Supporting Evidence: PMID:21630211 Bid, Apaf-1 and cleaved caspase-9 were restricted in the SG |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mitochondrial location transferred from human CASP9; caspase-9 redistributes to mitochondria during apoptosis and procaspase-9 processing in mitochondria is reported in rat hepatocytes. Non-core. Reason: Root organelle term; the source is the human IDA (fluorescence and fractionation) showing apoptosis-triggered redistribution of caspase-9 to mitochondria, and rat hepatocyte fractionation reports procaspase-9 cleavage in mitochondria. The organelle claim holds, but the core activity is in the cytosolic apoptosome, so it is non-core. The is_active_in qualifier is generous; the sub-compartment is not resolved (an ER-marker control is not described in the abstracts), so no sub-compartment term is added. Supporting Evidence: PMID:12782307 The activation of apoptosis with rotenone triggers the redistribution of caspase-9 to mitochondria PMID:18316105 Procaspase-9 underwent cleavage in mitochondria and translocation to the nucleus, where increased caspase-9 activity was detected |
| GO:0005739 mitochondrion | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO mitochondrion from human CASP9; supported but peripheral. Reason: As for the IEA row: apoptosis-associated mitochondrial redistribution is documented for human and rat caspase-9, but the enzyme functions in the cytosolic apoptosome. Supporting Evidence: PMID:12782307 The activation of apoptosis with rotenone triggers the redistribution of caspase-9 to mitochondria PMID:18316105 Procaspase-9 underwent cleavage in mitochondria and translocation to the nucleus, where increased caspase-9 activity was detected |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Cytosol is where the Apaf-1 apoptosome assembles and activates caspase-9; correct core location. Reason: The apoptosome is part of the cytosol, and caspase-9 is a soluble cytoplasmic protein before recruitment. The IBA node for the initiator/executioner caspase clade is consistent with this. Supporting Evidence: PMID:12782307 caspase-9 is in the cytoplasm of non-apoptotic pituitary cells PMID:9390557 Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic cytosol annotation; correct. Reason: Consistent with the cytosolic apoptosome function. Supporting Evidence: PMID:12782307 caspase-9 is in the cytoplasm of non-apoptotic pituitary cells |
| GO:0005829 cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: ISO cytosol from mouse Casp9; correct. Reason: Mouse cytosolic extracts lacking Casp9 fail to cleave Casp3 after cytochrome c addition, placing the activity in the cytosol. Supporting Evidence: PMID:9708735 the cytochrome c-mediated cleavage of Casp3 is absent in the cytosolic extracts of Casp9-deficient cells but is restored after addition of in vitro-translated Casp9 |
| GO:0005829 cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: ISO cytosol from human CASP9; correct. Reason: Human caspase-9 is cytoplasmic and functions in the cytosolic apoptosome. Supporting Evidence: PMID:12782307 caspase-9 is in the cytoplasm of non-apoptotic pituitary cells |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | MODIFY | Summary: True but general; caspase-9 proteolysis is the processing (maturation by cleavage) of executioner procaspases and of itself. Reason: Proteolysis is correct for a caspase but uninformative. The specific process caspase-9 carries out is protein processing (GO:0016485, is_a proteolysis and protein maturation): cleavage of procaspase-3 and -7 intersubunit linkers and its own autoprocessing on the apoptosome. The gene already carries GO:0016485 by IDA. Proposed replacements: protein processing Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 PMID:16352606 the latter complex directly cleaves/activates procaspase-7 |
| GO:0006915 apoptotic process | IBA GO_REF:0000033 | MODIFY | Summary: Caspase-9 participates in apoptosis specifically as the initiator of the intrinsic pathway; refine. Reason: Correct but general. Caspase-9 is the apical caspase of the mitochondrial (intrinsic) pathway, activated on the cytochrome c/Apaf-1 apoptosome; GO:0097193 intrinsic apoptotic signaling pathway, which this gene already carries, is the specific process. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000047947 SUPPORTS TRANSFER Caspase-family node; apoptotic process is inherited by all members, but caspase-9 has the more specific intrinsic-pathway role. RGD:61867 SUPPORTS TRANSFER Rat Casp9 appears among its own descendant evidence, as expected. UniProtKB:P55211 SUPPORTS TRANSFER Human CASP9 is the apoptosome initiator caspase. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:9390557 caspase-9 is the most upstream member of the apoptotic protease cascade that is triggered by cytochrome c and dATP PMID:9708735 Casp9 is a critical upstream activator of the caspase cascade in vivo |
| GO:0006915 apoptotic process | IEA GO_REF:0000120 | MODIFY | Summary: Electronic apoptotic process; refine to intrinsic apoptotic signaling pathway. Reason: Correct but general. Caspase-9 is the apical caspase of the mitochondrial (intrinsic) pathway, activated on the cytochrome c/Apaf-1 apoptosome; GO:0097193 intrinsic apoptotic signaling pathway, which this gene already carries, is the specific process. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:9390557 caspase-9 is the most upstream member of the apoptotic protease cascade that is triggered by cytochrome c and dATP |
| GO:0006915 apoptotic process | ISO GO_REF:0000121 | MODIFY | Summary: ISO from mouse (acts upstream of or within apoptotic process); the mouse knockout supports the intrinsic-pathway role; refine. Reason: Correct but general. Caspase-9 is the apical caspase of the mitochondrial (intrinsic) pathway, activated on the cytochrome c/Apaf-1 apoptosome; GO:0097193 intrinsic apoptotic signaling pathway, which this gene already carries, is the specific process. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1277950 SUPPORTS TRANSFER Mouse Casp9 knockout phenotypes (reduced apoptosis, loss of Casp3 activation) support the transfer; the term is broader than the evidence. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:9708735 Casp9 is a critical upstream activator of the caspase cascade in vivo |
| GO:0006915 apoptotic process | ISO GO_REF:0000121 | MODIFY | Summary: ISO from human apoptotic process; refine to intrinsic apoptotic signaling pathway. Reason: Correct but general. Caspase-9 is the apical caspase of the mitochondrial (intrinsic) pathway, activated on the cytochrome c/Apaf-1 apoptosome; GO:0097193 intrinsic apoptotic signaling pathway, which this gene already carries, is the specific process. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P55211 SUPPORTS TRANSFER Human CASP9 apoptotic role is well established; the specific term is GO:0097193. Proposed replacements: intrinsic apoptotic signaling pathway Supporting Evidence: PMID:9390557 caspase-9 is the most upstream member of the apoptotic protease cascade that is triggered by cytochrome c and dATP |
| GO:0006974 DNA damage response | IEA GO_REF:0000120 | MODIFY | Summary: True only as the apoptotic arm of the DNA damage response; refine to intrinsic apoptotic signaling pathway in response to DNA damage. Reason: Caspase-9 takes part in the DNA damage response only as the apoptotic arm: DNA damage-induced apoptosis requires caspase-9, and ABL1 phosphorylation of caspase-9 (Tyr153 in human, conserved as Tyr191 in rat) promotes its autoprocessing after genotoxic stress. The precise term is GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage (is_a GO:0006974), which this gene already carries; the bare DNA damage response term is true but general. Proposed replacements: intrinsic apoptotic signaling pathway in response to DNA damage Supporting Evidence: PMID:15657060 caspase-9 autoprocessing is regulated by c-Abl in the apoptotic response to genotoxic stress PMID:11092819 DNA damage-induced neural precursor cell apoptosis, both in vitro and in vivo, was critically dependent on p53 and caspase 9 |
| GO:0006974 DNA damage response | ISO GO_REF:0000121 | MODIFY | Summary: ISO from mouse (acts upstream of or within DNA damage response); refine to the DNA damage-induced intrinsic apoptotic pathway. Reason: Caspase-9 takes part in the DNA damage response only as the apoptotic arm: DNA damage-induced apoptosis requires caspase-9, and ABL1 phosphorylation of caspase-9 (Tyr153 in human, conserved as Tyr191 in rat) promotes its autoprocessing after genotoxic stress. The precise term is GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage (is_a GO:0006974), which this gene already carries; the bare DNA damage response term is true but general. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1277950 SUPPORTS TRANSFER Mouse neural precursor apoptosis after DNA damage requires Casp9; the evidence is for the apoptotic response, a more specific term. Proposed replacements: intrinsic apoptotic signaling pathway in response to DNA damage Supporting Evidence: PMID:11092819 DNA damage-induced neural precursor cell apoptosis, both in vitro and in vivo, was critically dependent on p53 and caspase 9 |
| GO:0006974 DNA damage response | ISO GO_REF:0000121 | MODIFY | Summary: ISO from human DNA damage response; refine as for the other rows. Reason: Caspase-9 takes part in the DNA damage response only as the apoptotic arm: DNA damage-induced apoptosis requires caspase-9, and ABL1 phosphorylation of caspase-9 (Tyr153 in human, conserved as Tyr191 in rat) promotes its autoprocessing after genotoxic stress. The precise term is GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage (is_a GO:0006974), which this gene already carries; the bare DNA damage response term is true but general. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P55211 SUPPORTS TRANSFER Human data (c-Abl-regulated caspase-9 autoprocessing after DNA damage) support the apoptotic response to DNA damage; the ABL1 site is conserved in rat. Proposed replacements: intrinsic apoptotic signaling pathway in response to DNA damage Supporting Evidence: PMID:15657060 caspase-9 autoprocessing is regulated by c-Abl in the apoptotic response to genotoxic stress file:rat/Casp9/Casp9-bioinformatics/RESULTS.md Human Tyr153 (phosphorylated by ABL1 after DNA damage) maps to rat Tyr191. |
| GO:0008233 peptidase activity | IEA GO_REF:0000120 | MODIFY | Summary: Peptidase activity is correct but general; refine to cysteine-type endopeptidase activity. Reason: Correct but general. Caspase-9 is a cysteine-type endopeptidase (catalytic Cys/His dyad conserved in rat) that cleaves after Asp within procaspase linkers; GO:0004197, already on this gene, is the specific activity. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: file:rat/Casp9/Casp9-bioinformatics/RESULTS.md Catalytic dyad conserved: human His237 maps to rat His275 and human Cys287 maps to rat Cys325 file:rat/Casp9/Casp9-uniprot.txt Belongs to the peptidase C14A family. |
| GO:0008233 peptidase activity | ISO GO_REF:0000121 | MODIFY | Summary: ISO peptidase activity from mouse; refine to cysteine-type endopeptidase activity. Reason: Correct but general. Caspase-9 is a cysteine-type endopeptidase (catalytic Cys/His dyad conserved in rat) that cleaves after Asp within procaspase linkers; GO:0004197, already on this gene, is the specific activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1277950 SUPPORTS TRANSFER Mouse Casp9 peptidase activity is real; the source term is less specific than the established endopeptidase activity. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: PMID:9708735 Casp9 is a critical upstream activator of the caspase cascade in vivo file:rat/Casp9/Casp9-bioinformatics/RESULTS.md Catalytic dyad conserved: human His237 maps to rat His275 and human Cys287 maps to rat Cys325 |
| GO:0008233 peptidase activity | ISO GO_REF:0000121 | MODIFY | Summary: ISO peptidase activity from human; refine to cysteine-type endopeptidase activity. Reason: Correct but general. Caspase-9 is a cysteine-type endopeptidase (catalytic Cys/His dyad conserved in rat) that cleaves after Asp within procaspase linkers; GO:0004197, already on this gene, is the specific activity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P55211 SUPPORTS TRANSFER Human CASP9 is an established cysteine-type endopeptidase. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 file:rat/Casp9/Casp9-bioinformatics/RESULTS.md Catalytic dyad conserved: human His237 maps to rat His275 and human Cys287 maps to rat Cys325 |
| GO:0008234 cysteine-type peptidase activity | IDA PMID:16336964 In vivo delivery of a XIAP (BIR3-RING) fusion protein contai... | MODIFY | Summary: Caspase-9 activation/activity measured in rat hippocampus after kainate seizures; refine to cysteine-type endopeptidase activity. Reason: Caspase activity assays (cleavage of LEHD-type peptide substrates after Asp, or of procaspases) measure endopeptidase activity of a cysteine protease. The claim is sound but GO:0004197 cysteine-type endopeptidase activity, already carried by this gene, is the precise term. Abstract only; the refinement does not depend on details of the assay because caspase-9 activity is endopeptidic by mechanism. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: PMID:16336964 KA triggered neuronal death in the ipsilateral CA3 subfield of the hippocampus and activation of caspase-3 and -9 file:rat/Casp9/Casp9-bioinformatics/RESULTS.md Catalytic dyad conserved: human His237 maps to rat His275 and human Cys287 maps to rat Cys325 |
| GO:0008234 cysteine-type peptidase activity | IDA PMID:18316105 Implication of caspases and subcellular compartments in tert... | MODIFY | Summary: Caspase-9 activity detected in nuclei of t-BHP-treated rat hepatocytes; refine to cysteine-type endopeptidase activity. Reason: Caspase activity assays (cleavage of LEHD-type peptide substrates after Asp, or of procaspases) measure endopeptidase activity of a cysteine protease. The claim is sound but GO:0004197 cysteine-type endopeptidase activity, already carried by this gene, is the precise term. Abstract only. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: PMID:18316105 Procaspase-9 underwent cleavage in mitochondria and translocation to the nucleus, where increased caspase-9 activity was detected file:rat/Casp9/Casp9-bioinformatics/RESULTS.md Catalytic dyad conserved: human His237 maps to rat His275 and human Cys287 maps to rat Cys325 |
| GO:0008234 cysteine-type peptidase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO cysteine-type peptidase activity from the C14A family signature; refine. Reason: Caspase activity assays (cleavage of LEHD-type peptide substrates after Asp, or of procaspases) measure endopeptidase activity of a cysteine protease. The claim is sound but GO:0004197 cysteine-type endopeptidase activity, already carried by this gene, is the precise term. Proposed replacements: cysteine-type endopeptidase activity Supporting Evidence: file:rat/Casp9/Casp9-uniprot.txt Belongs to the peptidase C14A family. file:rat/Casp9/Casp9-bioinformatics/RESULTS.md Catalytic dyad conserved: human His237 maps to rat His275 and human Cys287 maps to rat Cys325 |
| GO:0008303 caspase complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Caspase complex: active caspase-9 is a p35/p10 heterotetramer, and it acts within the apoptosome holoenzyme. Accurate but the apoptosome is the informative complex. Reason: GO:0008303 covers any complex containing a caspase that confers aspartyl-specific peptidase activity. Processed caspase-9 subunits and the caspase-9-bearing apoptosome both meet this definition. The functionally informative complex, GO:0043293 apoptosome, is captured separately; apoptosome is not an is_a child of caspase complex in GO, so this row is kept rather than modified. Supporting Evidence: PMID:21827945 disk assembly and pc-9 binding create an asymmetric proteolysis machine |
| GO:0008303 caspase complex | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO caspase complex from human CASP9 (and its processed chain); kept as non-core. Reason: As for the IEA row. Supporting Evidence: PMID:21827945 disk assembly and pc-9 binding create an asymmetric proteolysis machine |
| GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Caspase-9 executes the intrinsic apoptotic response to DNA damage; accurate, kept as non-core context of the core intrinsic-pathway role. Reason: Caspase-9 is required for DNA damage-induced apoptosis (mouse neural precursors, Casp9-/- ES cells and fibroblasts after gamma or UV irradiation), and DNA damage-induced autoprocessing of caspase-9 is regulated by c-Abl. The term is accurate; it is a stimulus-specific instance of the core intrinsic pathway role, so non-core. Supporting Evidence: PMID:11092819 DNA damage-induced neural precursor cell apoptosis, both in vitro and in vivo, was critically dependent on p53 and caspase 9 PMID:15657060 caspase-9 autoprocessing is regulated by c-Abl in the apoptotic response to genotoxic stress |
| GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from human; accurate, non-core. Reason: Caspase-9 is required for DNA damage-induced apoptosis (mouse neural precursors, Casp9-/- ES cells and fibroblasts after gamma or UV irradiation), and DNA damage-induced autoprocessing of caspase-9 is regulated by c-Abl. The term is accurate; it is a stimulus-specific instance of the core intrinsic pathway role, so non-core. Supporting Evidence: PMID:15657060 caspase-9 autoprocessing is regulated by c-Abl in the apoptotic response to genotoxic stress |
| GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from human; accurate, non-core. Reason: Caspase-9 is required for DNA damage-induced apoptosis (mouse neural precursors, Casp9-/- ES cells and fibroblasts after gamma or UV irradiation), and DNA damage-induced autoprocessing of caspase-9 is regulated by c-Abl. The term is accurate; it is a stimulus-specific instance of the core intrinsic pathway role, so non-core. Supporting Evidence: PMID:15657060 caspase-9 autoprocessing is regulated by c-Abl in the apoptotic response to genotoxic stress file:rat/Casp9/Casp9-bioinformatics/RESULTS.md Human Tyr153 (phosphorylated by ABL1 after DNA damage) maps to rat Tyr191. |
| GO:0009411 response to UV | IEA GO_REF:0000117 | MODIFY | Summary: ARBA response to UV; caspase-9 acts in the cellular apoptotic response to UV; refine to cellular response to UV. Reason: Caspase-9 is required for UV-induced apoptosis of embryonic stem cells and fibroblasts. The response is cellular (apoptosis of the irradiated cell), so GO:0034644 cellular response to UV (is_a GO:0009411), already on this gene, is the precise form. Proposed replacements: cellular response to UV Supporting Evidence: PMID:9708736 Casp9-/- embryonic stem cells and embryonic fibroblasts are resistant to several apoptotic stimuli, including UV and gamma irradiation |
| GO:0009411 response to UV | ISO GO_REF:0000121 | MODIFY | Summary: ISO from mouse (acts upstream of or within response to UV); refine to cellular response to UV. Reason: Caspase-9 is required for UV-induced apoptosis of embryonic stem cells and fibroblasts. The response is cellular (apoptosis of the irradiated cell), so GO:0034644 cellular response to UV (is_a GO:0009411), already on this gene, is the precise form. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1277950 SUPPORTS TRANSFER Casp9-/- ES cells and fibroblasts resist UV-induced apoptosis; this is a cellular response. Proposed replacements: cellular response to UV Supporting Evidence: PMID:9708736 Casp9-/- embryonic stem cells and embryonic fibroblasts are resistant to several apoptotic stimuli, including UV and gamma irradiation |
| GO:0010996 response to auditory stimulus | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO response to auditory stimulus from another RGD species record; caspase-9 activation in noise-damaged cochlea would be an apoptosis read-out, not a role in hearing. Reason: The source annotation (RGD:8882041, a non-rat RGD gene record) could not be inspected. Caspase-9 has no known role in sensing or responding to sound; noise- or drug-induced cochlear hair cell death involves caspase activation, and in the one rat cochlear study cited here caspase-9 inhibition did not reduce hair cell loss. The row is at best a context annotation of the apoptotic role. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: RGD:8882041 UNRESOLVED Source record and its supporting paper were not available in this session. Supporting Evidence: PMID:17869439 a caspase-3 inhibitor decreased caspase-3 activation and hair cell loss induced by gentamicin and an XIAP inhibitor, but caspase-8 and -9 inhibitors did not |
| GO:0016485 protein processing | IDA PMID:18316105 Implication of caspases and subcellular compartments in tert... | ACCEPT | Summary: Caspase-9 performs protein processing: it cleaves executioner procaspases and autoprocesses on the apoptosome. Accepted as a core process. Reason: Protein processing (maturation by peptide-bond cleavage) is what caspase-9 does to procaspase-3, procaspase-7 and to itself. The rat hepatocyte study (abstract only) reports procaspase-9 cleavage in mitochondria with increased caspase-9 activity; in that model caspase-3/7 were not activated, so the curated observation is probably caspase-9 processing itself, which is still caspase-9 doing the work. The function is established for the orthologs, so the curator's call is deferred to. Supporting Evidence: PMID:18316105 Procaspase-9 underwent cleavage in mitochondria and translocation to the nucleus, where increased caspase-9 activity was detected PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 PMID:16352606 the latter complex directly cleaves/activates procaspase-7 |
| GO:0019901 protein kinase binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Caspase-9 binds ABL1 (c-Abl), which phosphorylates it after DNA damage; the site is conserved in rat. Non-core. Reason: Human caspase-9 binds the ABL1 tyrosine kinase directly and is phosphorylated by it on Tyr153, which is conserved in rat (Tyr191). The binding is real but reflects caspase-9 being a kinase substrate; it is a regulatory input, not part of caspase-9's own activity, so non-core. The human AKT1 inhibitory site Ser196 is not conserved in rat (Trp234), so AKT binding should not be assumed for rat. Supporting Evidence: PMID:15657060 The present results demonstrate that c-Abl binds directly to caspase-9 file:rat/Casp9/Casp9-bioinformatics/RESULTS.md Human Tyr153 (phosphorylated by ABL1 after DNA damage) maps to rat Tyr191. |
| GO:0019901 protein kinase binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO protein kinase binding from human CASP9 (c-Abl); non-core. Reason: Human caspase-9 binds the ABL1 tyrosine kinase directly and is phosphorylated by it on Tyr153, which is conserved in rat (Tyr191). The binding is real but reflects caspase-9 being a kinase substrate; it is a regulatory input, not part of caspase-9's own activity, so non-core. The human AKT1 inhibitory site Ser196 is not conserved in rat (Trp234), so AKT binding should not be assumed for rat. Supporting Evidence: PMID:15657060 The present results demonstrate that c-Abl binds directly to caspase-9 file:rat/Casp9/Casp9-bioinformatics/RESULTS.md Human Tyr153 (phosphorylated by ABL1 after DNA damage) maps to rat Tyr191. |
| GO:0032025 response to cobalt ion | IEP PMID:18598848 Estradiol protects PC12 cells against CoCl2-induced apoptosi... | MARK AS OVER ANNOTATED | Summary: CoCl2-induced caspase-9 activity in PC12 cells is limited by estradiol; an apoptosis read-out, not a role in the response to cobalt. Reason: The cited rat study measures caspase-9 protein, cleavage or LEHD-substrate activity as a read-out of intrinsic apoptosis in this experimental model. That shows caspase-9 is activated when cells die under the condition, not that caspase-9 performs any step of the organism's response to the stimulus; its own activity is the apoptotic cascade. The row is a context annotation of the apoptotic role, so it is marked as an over-annotation rather than removed. Abstract only. 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: Estradiol reduces CoCl2-induced caspase-9 activity in PC12 cells; caspase-9 does not participate in the estradiol response. Reason: The cited rat study measures caspase-9 protein, cleavage or LEHD-substrate activity as a read-out of intrinsic apoptosis in this experimental model. That shows caspase-9 is activated when cells die under the condition, not that caspase-9 performs any step of the organism's response to the stimulus; its own activity is the apoptotic cascade. The row is a context annotation of the apoptotic role, so it is marked as an over-annotation rather than removed. Abstract only; estradiol acts upstream through ROS, Bcl-2 family and Akt signaling. Supporting Evidence: PMID:18598848 limited the activities of the caspase cascades, such as caspase-8, -9 and -3 |
| GO:0032496 response to lipopolysaccharide | IEP PMID:18289516 Caspase activation in fetal rat brain following experimental... | MARK AS OVER ANNOTATED | Summary: Caspase-9 activity rises in fetal rat brain after maternal LPS; an apoptosis read-out, not a role in the LPS response. Reason: The cited rat study measures caspase-9 protein, cleavage or LEHD-substrate activity as a read-out of intrinsic apoptosis in this experimental model. That shows caspase-9 is activated when cells die under the condition, not that caspase-9 performs any step of the organism's response to the stimulus; its own activity is the apoptotic cascade. The row is a context annotation of the apoptotic role, so it is marked as an over-annotation rather than removed. Abstract only. Supporting Evidence: PMID:18289516 Caspase activity assays demonstrated rapid increases in (i) caspases-9 and -10 within 1 h file:rat/Casp9/Casp9-deep-research-manual.md The many "response to X" IEP annotations reflect use of caspase-9 activation as a cell-death marker rather than participation in those responses. |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | MODIFY | Summary: Protein-containing complex is too general; the relevant complex is the apoptosome. Reason: Correct but uninformative. The complex in question is the apoptosome (GO:0043293, is_a protein-containing complex), which this gene already carries; caspase-9 is recruited to it through CARD-CARD binding to Apaf-1. Proposed replacements: apoptosome Supporting Evidence: PMID:9390557 Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation PMID:21827945 Activation of procaspase-9 on the apoptosome is a pivotal step in the intrinsic cell death pathway |
| GO:0032991 protein-containing complex | ISO GO_REF:0000121 | MODIFY | Summary: ISO protein-containing complex from human; refine to apoptosome. Reason: Correct but uninformative. The complex in question is the apoptosome (GO:0043293, is_a protein-containing complex), which this gene already carries; caspase-9 is recruited to it through CARD-CARD binding to Apaf-1. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P55211 SUPPORTS TRANSFER Human CASP9 complex membership is the apoptosome. Proposed replacements: apoptosome Supporting Evidence: PMID:9390557 Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation PMID:21827945 Activation of procaspase-9 on the apoptosome is a pivotal step in the intrinsic cell death pathway |
| GO:0034349 glial cell apoptotic process | IEP PMID:18931364 Bax and Bid act in synergy to bring about T11TS-mediated gli... | MARK AS OVER ANNOTATED | Summary: Active caspase-9 is detected in glioma cells undergoing T11TS-induced apoptosis; cell-type context for the intrinsic apoptotic role. Reason: Abstract only. Detection of active caspase-9 in dying glioma cells shows that the intrinsic pathway is engaged in these cells. Caspase-9 participates in apoptosis of many cell types; a glial-cell-specific apoptotic process term adds cell-type context, not a distinct function, and the evidence is an expression observation. Supporting Evidence: PMID:18931364 the presence of active caspase-9 and active caspase-3 in all the T11TS-treated tumor-bearing groups |
| GO:0034644 cellular response to UV | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Caspase-9 executes UV-induced apoptosis; accurate, non-core. Reason: Caspase-9 is required for UV-induced apoptosis of ES cells and fibroblasts, and UV is among the genotoxic stimuli whose apoptotic response it executes. Accurate but a stimulus-specific context of the intrinsic pathway role, so non-core. Supporting Evidence: PMID:9708736 Casp9-/- embryonic stem cells and embryonic fibroblasts are resistant to several apoptotic stimuli, including UV and gamma irradiation |
| GO:0034644 cellular response to UV | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from human; accurate, non-core. Reason: Caspase-9 is required for UV-induced apoptosis of ES cells and fibroblasts, and UV is among the genotoxic stimuli whose apoptotic response it executes. Accurate but a stimulus-specific context of the intrinsic pathway role, so non-core. Supporting Evidence: PMID:9708736 Casp9-/- embryonic stem cells and embryonic fibroblasts are resistant to several apoptotic stimuli, including UV and gamma irradiation PMID:15657060 caspase-9 autoprocessing is regulated by c-Abl in the apoptotic response to genotoxic stress |
| GO:0042770 signal transduction in response to DNA damage | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Caspase-9 is downstream of DNA damage signaling, not a transducer of it; over-annotation. Reason: GO:0042770 is the cascade induced by detecting DNA damage (sensor kinases, checkpoint mediators). Caspase-9 acts downstream as the executing protease of the apoptotic outcome; it is phosphorylated by c-Abl but does not transduce the damage signal itself. GO:0008630, not a descendant of GO:0042770, is the appropriate term and is already present. Supporting Evidence: PMID:15657060 caspase-9 autoprocessing is regulated by c-Abl in the apoptotic response to genotoxic stress |
| GO:0042770 signal transduction in response to DNA damage | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO from human; over-annotation as for the IEA row. Reason: GO:0042770 is the cascade induced by detecting DNA damage (sensor kinases, checkpoint mediators). Caspase-9 acts downstream as the executing protease of the apoptotic outcome; it is phosphorylated by c-Abl but does not transduce the damage signal itself. GO:0008630, not a descendant of GO:0042770, is the appropriate term and is already present. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P55211 SUPPORTS SOURCE BUT NOT TARGET The human evidence (c-Abl regulation of caspase-9 autoprocessing) shows caspase-9 is a target of damage signaling, which is not the same as transducing it. Supporting Evidence: PMID:15657060 caspase-9 autoprocessing is regulated by c-Abl in the apoptotic response to genotoxic stress |
| GO:0042802 identical protein binding | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Caspase-9 homodimerizes and oligomerizes on the apoptosome; identical protein binding transferred from human is plausible but non-core. Reason: Activation of caspase-9 involves self-association of procaspase-9 molecules on the apoptosome, consistent with the human self-interaction evidence behind this ISO row. Self-binding is part of the activation mechanism rather than the enzyme's function, so non-core. Supporting Evidence: PMID:21827945 Activation of procaspase-9 on the apoptosome is a pivotal step in the intrinsic cell death pathway |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000002 | MODIFY | Summary: CARD-domain InterPro2GO regulation of apoptotic process; refine to positive regulation of execution phase of apoptosis. Reason: The CARD mapping gives an unsigned, general term. Caspase-9 promotes apoptosis by activating executioner caspases; GO:1900119 positive regulation of execution phase of apoptosis, already on this gene, is the specific and correctly signed process. Proposed replacements: positive regulation of execution phase of apoptosis Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 PMID:16352606 the latter complex directly cleaves/activates procaspase-7 |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000120 | MODIFY | Summary: Electronic positive regulation of apoptotic process; refine to positive regulation of execution phase of apoptosis. Reason: Correct but general. Caspase-9 promotes apoptosis by activating executioner caspases; GO:1900119 positive regulation of execution phase of apoptosis, already on this gene, is the specific and correctly signed process. Proposed replacements: positive regulation of execution phase of apoptosis Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 |
| GO:0043065 positive regulation of apoptotic process | IMP PMID:17869439 Role of inhibitor of apoptosis protein in gentamicin-induced... | MODIFY | Summary: Caspase-9 positively regulates apoptosis (refine to execution phase, as for the other rows), but the cited gentamicin cochlea paper does not visibly support it: its abstract says caspase-9 inhibitors did not reduce hair cell loss. Reason: Abstract only. The abstract reports that a caspase-3 inhibitor reduced hair cell loss induced by gentamicin plus an XIAP inhibitor, but caspase-8 and caspase-9 inhibitors did not. That reads as evidence against a requirement for caspase-9 in this model. The full text may contain another experiment (for example gentamicin alone) that the curator used, so the row is not removed. The claim itself, that caspase-9 promotes apoptosis, is true of the gene and is refined here exactly as on the IEA and ISO rows for this term (Caspase-9 promotes apoptosis by activating executioner caspases; GO:1900119 positive regulation of execution phase of apoptosis, already on this gene, is the specific and correctly signed process.) The doubt about this paper's support is recorded as a source defect for RGD to check. Proposed replacements: positive regulation of execution phase of apoptosis Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 PMID:16352606 the latter complex directly cleaves/activates procaspase-7 |
| GO:0043065 positive regulation of apoptotic process | ISO GO_REF:0000121 | MODIFY | Summary: ISO positive regulation of apoptotic process from human; refine to positive regulation of execution phase of apoptosis. Reason: Correct but general. Caspase-9 promotes apoptosis by activating executioner caspases; GO:1900119 positive regulation of execution phase of apoptosis, already on this gene, is the specific and correctly signed process. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P55211 SUPPORTS TRANSFER Human CASP9 promotes apoptosis by activating executioner caspases; the specific term is GO:1900119. Proposed replacements: positive regulation of execution phase of apoptosis Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 PMID:16352606 the latter complex directly cleaves/activates procaspase-7 |
| GO:0043293 apoptosome | IEA GO_REF:0000107 | ACCEPT | Summary: Caspase-9 is the catalytic subunit of the apoptosome; core complex. Reason: Caspase-9 is recruited to the cytochrome c/Apaf-1 apoptosome through CARD-CARD interaction and is activated there; the apoptosome is defined as Apaf-1 heptamer bound to cytochrome c and caspase-9. Supporting Evidence: PMID:9390557 Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation PMID:21827945 Activation of procaspase-9 on the apoptosome is a pivotal step in the intrinsic cell death pathway |
| GO:0043293 apoptosome | ISO GO_REF:0000121 | ACCEPT | Summary: ISO apoptosome from human CASP9; core complex. Reason: Caspase-9 is recruited to the cytochrome c/Apaf-1 apoptosome through CARD-CARD interaction and is activated there; the apoptosome is defined as Apaf-1 heptamer bound to cytochrome c and caspase-9. Supporting Evidence: PMID:9390557 Caspase-9 and Apaf-1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome c and dATP, an event that leads to caspase-9 activation PMID:21827945 Activation of procaspase-9 on the apoptosome is a pivotal step in the intrinsic cell death pathway |
| GO:0043293 apoptosome | ISO GO_REF:0000121 | ACCEPT | Summary: ISO apoptosome from human CASP9 processed chain; core complex. Reason: Caspase-9 is recruited to the cytochrome c/Apaf-1 apoptosome through CARD-CARD interaction and is activated there; the apoptosome is defined as Apaf-1 heptamer bound to cytochrome c and caspase-9. Supporting Evidence: PMID:21827945 disk assembly and pc-9 binding create an asymmetric proteolysis machine |
| GO:0043525 positive regulation of neuron apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Caspase-9 drives neuronal apoptosis; accurate, kept as non-core cell-type context. Reason: Caspase-9 is required for developmental and DNA damage-induced neuronal apoptosis (Casp9 knockout brain overgrowth; neural precursor apoptosis after DNA damage), and in rat hippocampus caspase-9 is activated in kainate-induced neuronal death. Accurate for a pro-apoptotic caspase in neurons, but a cell-type context of the core role, so non-core. Supporting Evidence: PMID:9708735 The majority of Casp9 knockout mice die perinatally with a markedly enlarged and malformed cerebrum caused by reduced apoptosis during brain development PMID:11092819 DNA damage-induced neural precursor cell apoptosis, both in vitro and in vivo, was critically dependent on p53 and caspase 9 PMID:16336964 KA triggered neuronal death in the ipsilateral CA3 subfield of the hippocampus and activation of caspase-3 and -9 |
| GO:0043525 positive regulation of neuron apoptotic process | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO from mouse; accurate, non-core. Reason: Caspase-9 is required for developmental and DNA damage-induced neuronal apoptosis (Casp9 knockout brain overgrowth; neural precursor apoptosis after DNA damage), and in rat hippocampus caspase-9 is activated in kainate-induced neuronal death. Accurate for a pro-apoptotic caspase in neurons, but a cell-type context of the core role, so non-core. Supporting Evidence: PMID:9708735 The majority of Casp9 knockout mice die perinatally with a markedly enlarged and malformed cerebrum caused by reduced apoptosis during brain development PMID:11092819 DNA damage-induced neural precursor cell apoptosis, both in vitro and in vivo, was critically dependent on p53 and caspase 9 |
| GO:0045471 response to ethanol | IEP PMID:30926569 Effect of saffron (stigma of Crocus sativus L.) aqueous extr... | MARK AS OVER ANNOTATED | Summary: Ethanol increases caspase-9 expression in rat kidney and liver; an apoptosis read-out, not a role in the ethanol response. Reason: The cited rat study measures caspase-9 protein, cleavage or LEHD-substrate activity as a read-out of intrinsic apoptosis in this experimental model. That shows caspase-9 is activated when cells die under the condition, not that caspase-9 performs any step of the organism's response to the stimulus; its own activity is the apoptotic cascade. The row is a context annotation of the apoptotic role, so it is marked as an over-annotation rather than removed. Abstract only. Supporting Evidence: PMID:30926569 The ethanol increased the expression of Bax/Bcl2 ratio, caspase-3, -8, and -9. file:rat/Casp9/Casp9-deep-research-manual.md The many "response to X" IEP annotations reflect use of caspase-9 activation as a cell-death marker rather than participation in those responses. |
| GO:0048513 animal organ development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA animal organ development; a consequence of caspase-9's apoptotic role, over-annotation. Reason: The ARBA rule propagates a broad developmental term. Casp9 knockout mice show brain malformation from reduced apoptosis, which is necessity evidence: caspase-9 executes cell death that development uses, but it performs no developmental step itself beyond apoptosis, which is already captured. Supporting Evidence: PMID:9708735 The majority of Casp9 knockout mice die perinatally with a markedly enlarged and malformed cerebrum caused by reduced apoptosis during brain development |
| GO:0048731 system development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA system development; over-annotation as for animal organ development. Reason: The ARBA rule propagates a broad developmental term. Casp9 knockout mice show brain malformation from reduced apoptosis, which is necessity evidence: caspase-9 executes cell death that development uses, but it performs no developmental step itself beyond apoptosis, which is already captured. Supporting Evidence: PMID:9708735 The majority of Casp9 knockout mice die perinatally with a markedly enlarged and malformed cerebrum caused by reduced apoptosis during brain development |
| GO:0051604 protein maturation | IEA GO_REF:0000107 | MODIFY | Summary: Caspase-9 matures executioner procaspases by cleavage; refine protein maturation to protein processing. Reason: Correct but general. Caspase-9 matures executioner procaspases (and itself) specifically by proteolytic cleavage, which is GO:0016485 protein processing (is_a protein maturation), already on this gene by IDA. Proposed replacements: protein processing Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 PMID:16352606 the latter complex directly cleaves/activates procaspase-7 |
| GO:0051604 protein maturation | ISO GO_REF:0000121 | MODIFY | Summary: ISO protein maturation from human; refine to protein processing. Reason: Correct but general. Caspase-9 matures executioner procaspases (and itself) specifically by proteolytic cleavage, which is GO:0016485 protein processing (is_a protein maturation), already on this gene by IDA. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P55211 SUPPORTS TRANSFER Human apoptosome-bound CASP9 cleaves procaspase-3 and -7; the maturation is by proteolysis. Proposed replacements: protein processing Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 PMID:16352606 the latter complex directly cleaves/activates procaspase-7 |
| GO:0071549 cellular response to dexamethasone stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Dexamethasone regulates Casp9 expression; the gene product does not take part in the dexamethasone response. Over-annotation. Reason: The mouse source reports that dexamethasone rapidly down-regulates Casp9 expression (via AP-4), an expression response of the gene rather than a function of caspase-9 in the cellular response to the glucocorticoid. Casp9 is required for dexamethasone-induced thymocyte apoptosis, but that is its apoptotic role in another context. Supporting Evidence: PMID:15944155 When the cells were treated with dexamethasone, a rapid down-regulation of AP-4 and Casp-9 was observed PMID:9708736 Casp9-/- thymocytes are also resistant to dexamethasone- and gamma irradiation-induced apoptosis |
| GO:0071549 cellular response to dexamethasone stimulus | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO from mouse; over-annotation as for the IEA row. Reason: The mouse source reports that dexamethasone rapidly down-regulates Casp9 expression (via AP-4), an expression response of the gene rather than a function of caspase-9 in the cellular response to the glucocorticoid. Casp9 is required for dexamethasone-induced thymocyte apoptosis, but that is its apoptotic role in another context. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1277950 SUPPORTS SOURCE BUT NOT TARGET The mouse IDA records dexamethasone-induced change in Casp9 expression; it is an expression response, not participation. Supporting Evidence: PMID:15944155 When the cells were treated with dexamethasone, a rapid down-regulation of AP-4 and Casp-9 was observed |
| GO:0071680 response to indole-3-methanol | IDA PMID:17297389 Suppression of mammary gland carcinogenesis by post-initiati... | MARK AS OVER ANNOTATED | Summary: Indole-3-carbinol raises caspase-9 activity in rat mammary gland; an activity read-out, recorded with IDA although it is an expression/response observation. Over-annotation. Reason: Abstract only. The study measured caspase activities after I3C treatment and found increased caspase-9 activity only in DMBA-initiated tumor-free mammary gland. This shows caspase-9 activity changes in response to the compound; caspase-9 does not perform any step of a response to indole-3-methanol. The evidence code IDA is unusual for this type of observation, which is normally IEP. Supporting Evidence: PMID:17297389 In the mammary gland of DMBA-initiated tumor-free rats, however, I3C treatment increased the levels of caspase-3&7 and caspase-9 activities |
| GO:0071887 leukocyte apoptotic process | IEP PMID:26861981 Time course of apoptosis induced by photodynamic therapy wit... | MARK AS OVER ANNOTATED | Summary: Cleaved caspase-9 rises in rat LT12 leukemia cells after photodynamic therapy; cell-type context for intrinsic apoptosis. Reason: Abstract only. Expression of cleaved caspase-9 during PDT-induced apoptosis of a leukemia line is an expression time course; leukocyte apoptotic process adds cell-type context to the general intrinsic apoptotic role rather than a distinct function. Supporting Evidence: PMID:26861981 with the expression peaks of cleaved caspase-7, caspase-9 and PARP at 4-6 h |
| GO:0072347 response to anesthetic | IEP PMID:27498600 Neuroprotective effects of caffeic acid phenethyl ester agai... | MARK AS OVER ANNOTATED | Summary: Caspase-9 expression changes in neonatal rat hippocampus after sevoflurane; an apoptosis read-out, not a role in the anesthetic response. Reason: The cited rat study measures caspase-9 protein, cleavage or LEHD-substrate activity as a read-out of intrinsic apoptosis in this experimental model. That shows caspase-9 is activated when cells die under the condition, not that caspase-9 performs any step of the organism's response to the stimulus; its own activity is the apoptotic cascade. The row is a context annotation of the apoptotic role, so it is marked as an over-annotation rather than removed. Abstract only. Supporting Evidence: PMID:27498600 were evaluated by western blotting following sevoflurane and CAPE treatment file:rat/Casp9/Casp9-deep-research-manual.md The many "response to X" IEP annotations reflect use of caspase-9 activation as a cell-death marker rather than participation in those responses. |
| GO:0097193 intrinsic apoptotic signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Core process: caspase-9 is the initiator caspase of the intrinsic (mitochondrial) apoptotic signaling pathway. Reason: Caspase-9 is the apical caspase of the intrinsic pathway: recruited by Apaf-1 after cytochrome c release and activated on the apoptosome, it cleaves procaspase-3 and -7. In rat models its inhibition blocks intrinsic apoptosis (endothelial cells after ischemia, t-BHP-treated hepatocytes). Supporting Evidence: PMID:9390557 caspase-9 is the most upstream member of the apoptotic protease cascade that is triggered by cytochrome c and dATP PMID:9708735 Casp9 is a critical upstream activator of the caspase cascade in vivo PMID:18316105 A caspase-9 inhibitor, Z-LEHD-FMK, also reduced t-BHP-induced apoptosis, suggesting that caspase-9 plays a critical role in this process |
| GO:0097193 intrinsic apoptotic signaling pathway | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from human; core process. Reason: Caspase-9 is the apical caspase of the intrinsic pathway: recruited by Apaf-1 after cytochrome c release and activated on the apoptosome, it cleaves procaspase-3 and -7. In rat models its inhibition blocks intrinsic apoptosis (endothelial cells after ischemia, t-BHP-treated hepatocytes). Supporting Evidence: PMID:9390557 caspase-9 is the most upstream member of the apoptotic protease cascade that is triggered by cytochrome c and dATP PMID:21827945 Activation of procaspase-9 on the apoptosome is a pivotal step in the intrinsic cell death pathway |
| GO:1900119 positive regulation of execution phase of apoptosis | IEA GO_REF:0000107 | ACCEPT | Summary: Caspase-9 activates executioner caspases and so positively regulates the execution phase; core. Reason: Caspase-9 activates the executioner caspases-3 and -7 that carry out the execution phase; positive regulation of execution phase of apoptosis is the GO convention for this initiator role. Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 PMID:16352606 the latter complex directly cleaves/activates procaspase-7 |
| GO:1900119 positive regulation of execution phase of apoptosis | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from human; core. Reason: Caspase-9 activates the executioner caspases-3 and -7 that carry out the execution phase; positive regulation of execution phase of apoptosis is the GO convention for this initiator role. Supporting Evidence: PMID:9390557 Activated caspase-9 in turn cleaves and activates caspase-3 PMID:16352606 the latter complex directly cleaves/activates procaspase-7 |
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Download this section (compressed HTML)Q: PMID:17869439 reports that caspase-9 inhibitors did not reduce gentamicin plus XIAP-inhibitor induced hair cell loss; which experiment in that paper supports RGD's IMP for positive regulation of apoptotic process?
Q: Human CASP9 Ser196 (AKT1 inhibitory site) aligns to Trp234 in rat. Is caspase-9 regulated by AKT in rat cells at all, and should the rat Reactome projection 'AKT phosphorylates targets in the cytosol' include caspase-9?
Q: Rat Casp9 has a ~38-residue longer CARD-p20 linker than human CASP9, with repeated PVVLGP-like motifs. Does this linker affect apoptosome-dependent activation or XIAP binding?
Experiment: Compare apoptosome activation and XIAP inhibition of recombinant rat and human caspase-9 in a reconstituted cytochrome c/Apaf-1/dATP system, including a rat linker-deletion mutant, to test whether the rodent-specific linker changes activation kinetics.
Type: in vitro reconstitution
Experiment: Test AKT-dependent phosphorylation of rat caspase-9 in rat cells (phospho-proteomics after growth-factor stimulation) to establish whether the absence of the Ser196 site removes this regulatory input in rodents.
Type: phosphoproteomics
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