BBC3 encodes PUMA, a short BH3-only BCL2-family apoptosis regulator induced by TP53 and by several p53-independent stress programs including ER stress. PUMA moves to mitochondria, where its BH3 helix binds and neutralizes pro-survival BCL2-family proteins such as BCL2, BCL2L1/Bcl-xL, MCL1, and BCL2L2/Bcl-w and can weakly but directly activate BAX or BAK. These activities promote BAX/BAK oligomerization, mitochondrial outer-membrane permeabilization, cytochrome-c release, apoptosome formation, and caspase activation during intrinsic apoptosis.
Definition: Binding to a pro-survival BCL2-family protein through a BH3-mediated interaction to inhibit that protein from sequestering pro-apoptotic BCL2-family effectors or activators.
Justification: BIM, BID, PUMA, BAD, NOXA, and related BH3-only proteins donate BH3 helices to the grooves of pro-survival BCL2 proteins and inhibit their anti-apoptotic activity. GO:0051434 BH3 domain binding annotates the groove-side receptor and is directionally wrong for the BH3-only ligand.
Parent term: molecular function inhibitor activity
Supporting Evidence:
Definition: Binding to a pro-apoptotic BCL2-family effector such as BAX or BAK to promote the conformational activation and oligomerization that drives apoptotic mitochondrial outer-membrane permeabilization.
Justification: Direct-activator BH3-only proteins donate a BH3 helix that activates BAX/BAK, but GO:0051434 BH3 domain binding annotates the groove-containing protein that recognizes a BH3 helix. A BID/BIM/PUMA-side molecular-function term would prevent these central interactions from collapsing to GO:0005515 protein binding.
Parent term: molecular function activator activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001836 release of cytochrome c from mitochondria | IDA PMID:11463392 PUMA, a novel proapoptotic gene, is induced by p53. | MODIFY | Summary: PUMA positively regulates cytochrome-c release by promoting BAX/BAK-dependent mitochondrial outer-membrane permeabilization. Reason: PUMA is upstream of the pore-forming BAX/BAK step, so the regulatory descendant is more accurate than annotating the release event itself. Proposed replacements: positive regulation of release of cytochrome c from mitochondria |
| GO:0005515 protein binding | IPI PMID:11463391 PUMA induces the rapid apoptosis of colorectal cancer cells. | MODIFY | Summary: PUMA uses its BH3 helix to engage and inhibit a pro-survival BCL2-family protein. Reason: This is a core BCL2-family inhibitory interaction, but GO:0005515 is generic and GO:0051434 BH3 domain binding describes the groove-side partner rather than the PUMA BH3 ligand. A PUMA-side pro-survival BCL2-family inhibitor MF is needed. Proposed replacements: pro-survival BCL2 family protein inhibitor activity |
| GO:0005515 protein binding | IPI PMID:11463391 PUMA induces the rapid apoptosis of colorectal cancer cells. | MODIFY | Summary: PUMA uses its BH3 helix to engage and inhibit a pro-survival BCL2-family protein. Reason: This is a core BCL2-family inhibitory interaction, but GO:0005515 is generic and GO:0051434 BH3 domain binding describes the groove-side partner rather than the PUMA BH3 ligand. A PUMA-side pro-survival BCL2-family inhibitor MF is needed. Proposed replacements: pro-survival BCL2 family protein inhibitor activity |
| GO:0005515 protein binding | IPI PMID:11463392 PUMA, a novel proapoptotic gene, is induced by p53. | MODIFY | Summary: PUMA uses its BH3 helix to engage and inhibit a pro-survival BCL2-family protein. Reason: This is a core BCL2-family inhibitory interaction, but GO:0005515 is generic and GO:0051434 BH3 domain binding describes the groove-side partner rather than the PUMA BH3 ligand. A PUMA-side pro-survival BCL2-family inhibitor MF is needed. Proposed replacements: pro-survival BCL2 family protein inhibitor activity |
| GO:0005515 protein binding | IPI PMID:15694340 Differential targeting of prosurvival Bcl-2 proteins by thei... | MODIFY | Summary: PUMA uses its BH3 helix to engage and inhibit a pro-survival BCL2-family protein. Reason: This is a core BCL2-family inhibitory interaction, but GO:0005515 is generic and GO:0051434 BH3 domain binding describes the groove-side partner rather than the PUMA BH3 ligand. A PUMA-side pro-survival BCL2-family inhibitor MF is needed. Proposed replacements: pro-survival BCL2 family protein inhibitor activity |
| GO:0005515 protein binding | IPI PMID:15694340 Differential targeting of prosurvival Bcl-2 proteins by thei... | MODIFY | Summary: PUMA uses its BH3 helix to engage and inhibit a pro-survival BCL2-family protein. Reason: This is a core BCL2-family inhibitory interaction, but GO:0005515 is generic and GO:0051434 BH3 domain binding describes the groove-side partner rather than the PUMA BH3 ligand. A PUMA-side pro-survival BCL2-family inhibitor MF is needed. Proposed replacements: pro-survival BCL2 family protein inhibitor activity |
| GO:0005515 protein binding | IPI PMID:15694340 Differential targeting of prosurvival Bcl-2 proteins by thei... | MODIFY | Summary: PUMA uses its BH3 helix to engage and inhibit a pro-survival BCL2-family protein. Reason: This is a core BCL2-family inhibitory interaction, but GO:0005515 is generic and GO:0051434 BH3 domain binding describes the groove-side partner rather than the PUMA BH3 ligand. A PUMA-side pro-survival BCL2-family inhibitor MF is needed. Proposed replacements: pro-survival BCL2 family protein inhibitor activity |
| GO:0005515 protein binding | IPI PMID:15694340 Differential targeting of prosurvival Bcl-2 proteins by thei... | MODIFY | Summary: PUMA uses its BH3 helix to engage and inhibit a pro-survival BCL2-family protein. Reason: This is a core BCL2-family inhibitory interaction, but GO:0005515 is generic and GO:0051434 BH3 domain binding describes the groove-side partner rather than the PUMA BH3 ligand. A PUMA-side pro-survival BCL2-family inhibitor MF is needed. Proposed replacements: pro-survival BCL2 family protein inhibitor activity |
| GO:0005515 protein binding | IPI PMID:16151013 PUMA couples the nuclear and cytoplasmic proapoptotic functi... | MODIFY | Summary: PUMA uses its BH3 helix to engage and inhibit a pro-survival BCL2-family protein. Reason: This is a core BCL2-family inhibitory interaction, but GO:0005515 is generic and GO:0051434 BH3 domain binding describes the groove-side partner rather than the PUMA BH3 ligand. A PUMA-side pro-survival BCL2-family inhibitor MF is needed. Proposed replacements: pro-survival BCL2 family protein inhibitor activity |
| GO:0005515 protein binding | IPI PMID:16608847 PUMA Dissociates Bax and Bcl-X(L) to induce apoptosis in col... | MODIFY | Summary: PUMA uses its BH3 helix to engage and inhibit a pro-survival BCL2-family protein. Reason: This is a core BCL2-family inhibitory interaction, but GO:0005515 is generic and GO:0051434 BH3 domain binding describes the groove-side partner rather than the PUMA BH3 ligand. A PUMA-side pro-survival BCL2-family inhibitor MF is needed. Proposed replacements: pro-survival BCL2 family protein inhibitor activity |
| GO:0005515 protein binding | IPI PMID:16697956 Mitochondria primed by death signals determine cellular addi... | UNDECIDED | Summary: The row reports a plausible PUMA interaction with a pro-survival BCL2-family protein, but the exact partner-specific experiment is not recoverable from the cached text. Reason: Do not reject an experimental IntAct IPI row from incomplete evidence. The row may belong under a PUMA-side pro-survival BCL2-family inhibitor term, but this needs the full figure or supplement to verify the exact PUMA partner. |
| GO:0005515 protein binding | IPI PMID:16697956 Mitochondria primed by death signals determine cellular addi... | UNDECIDED | Summary: The row reports a plausible PUMA interaction with a pro-survival BCL2-family protein, but the exact partner-specific experiment is not recoverable from the cached text. Reason: Do not reject an experimental IntAct IPI row from incomplete evidence. The row may belong under a PUMA-side pro-survival BCL2-family inhibitor term, but this needs the full figure or supplement to verify the exact PUMA partner. |
| GO:0005515 protein binding | IPI PMID:16697956 Mitochondria primed by death signals determine cellular addi... | UNDECIDED | Summary: The row reports a plausible PUMA interaction with a pro-survival BCL2-family protein, but the exact partner-specific experiment is not recoverable from the cached text. Reason: Do not reject an experimental IntAct IPI row from incomplete evidence. The row may belong under a PUMA-side pro-survival BCL2-family inhibitor term, but this needs the full figure or supplement to verify the exact PUMA partner. |
| GO:0005515 protein binding | IPI PMID:16697956 Mitochondria primed by death signals determine cellular addi... | UNDECIDED | Summary: The row reports a plausible PUMA interaction with a pro-survival BCL2-family protein, but the exact partner-specific experiment is not recoverable from the cached text. Reason: Do not reject an experimental IntAct IPI row from incomplete evidence. The row may belong under a PUMA-side pro-survival BCL2-family inhibitor term, but this needs the full figure or supplement to verify the exact PUMA partner. |
| GO:0005515 protein binding | IPI PMID:17177603 DNA damage-induced Bcl-xL deamidation is mediated by NHE-1 a... | MODIFY | Summary: PUMA uses its BH3 helix to engage and inhibit a pro-survival BCL2-family protein. Reason: This is a core BCL2-family inhibitory interaction, but GO:0005515 is generic and GO:0051434 BH3 domain binding describes the groove-side partner rather than the PUMA BH3 ligand. A PUMA-side pro-survival BCL2-family inhibitor MF is needed. Proposed replacements: pro-survival BCL2 family protein inhibitor activity |
| GO:0005515 protein binding | IPI PMID:17289999 Apoptosis initiated when BH3 ligands engage multiple Bcl-2 h... | MODIFY | Summary: PUMA uses its BH3 helix to engage and inhibit a pro-survival BCL2-family protein. Reason: This is a core BCL2-family inhibitory interaction, but GO:0005515 is generic and GO:0051434 BH3 domain binding describes the groove-side partner rather than the PUMA BH3 ligand. A PUMA-side pro-survival BCL2-family inhibitor MF is needed. Proposed replacements: pro-survival BCL2 family protein inhibitor activity |
| GO:0005515 protein binding | IPI PMID:20153921 EGFR and EGFRvIII interact with PUMA to inhibit mitochondria... | REMOVE | Summary: EGFR can sequester PUMA in glioblastoma cells, but this antagonistic tumor interaction is not PUMA's mitochondrial BH3-only activity. Reason: A contextual sequestration edge to EGFR should not be retained as an unqualified GO:0005515 molecular function for PUMA. |
| GO:0005515 protein binding | IPI PMID:20627101 The fast-mobility isoform of mouse Mcl-1 is a mitochondrial ... | UNDECIDED | Summary: This imported row reports interaction with a mouse MCL1 isoform, but the cached abstract does not verify a PUMA-specific experiment. Reason: The full text is needed to decide whether this exact xenologous IPI row supports the PUMA-side pro-survival BCL2-family inhibitor activity. |
| GO:0005515 protein binding | IPI PMID:22516262 Chemical genomics identifies small-molecule MCL1 repressors ... | UNDECIDED | Summary: The cached full text supports MCL1/PUMA biology in the paper, but does not expose a row-specific BCL-xL/PUMA assay. Reason: Leave this experimental IPI row unresolved until the source table or figure that drove the IntAct BCL2L1 import is checked. |
| GO:0005515 protein binding | IPI PMID:22516262 Chemical genomics identifies small-molecule MCL1 repressors ... | MODIFY | Summary: PUMA uses its BH3 helix to engage and inhibit a pro-survival BCL2-family protein. Reason: This is a core BCL2-family inhibitory interaction, but GO:0005515 is generic and GO:0051434 BH3 domain binding describes the groove-side partner rather than the PUMA BH3 ligand. A PUMA-side pro-survival BCL2-family inhibitor MF is needed. Proposed replacements: pro-survival BCL2 family protein inhibitor activity |
| GO:0005515 protein binding | IPI PMID:26431330 Subcellular localization of PUMA regulates its pro-apoptotic... | MODIFY | Summary: PUMA uses its BH3 helix to engage and inhibit a pro-survival BCL2-family protein. Reason: This is a core BCL2-family inhibitory interaction, but GO:0005515 is generic and GO:0051434 BH3 domain binding describes the groove-side partner rather than the PUMA BH3 ligand. A PUMA-side pro-survival BCL2-family inhibitor MF is needed. Proposed replacements: pro-survival BCL2 family protein inhibitor activity |
| GO:0005515 protein binding | IPI PMID:26431330 Subcellular localization of PUMA regulates its pro-apoptotic... | MODIFY | Summary: PUMA uses its BH3 helix to engage and inhibit a pro-survival BCL2-family protein. Reason: This is a core BCL2-family inhibitory interaction, but GO:0005515 is generic and GO:0051434 BH3 domain binding describes the groove-side partner rather than the PUMA BH3 ligand. A PUMA-side pro-survival BCL2-family inhibitor MF is needed. Proposed replacements: pro-survival BCL2 family protein inhibitor activity |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: This is a high-throughput interactome edge that is not sufficient to define a PUMA molecular function. Reason: Large-scale interaction mapping can report candidate BCL2-family edges, but this row lacks the focused validation and BH3-dependent mechanism needed to curate a PUMA-side apoptotic inhibitor activity. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: This is a high-throughput interactome edge that is not sufficient to define a PUMA molecular function. Reason: Large-scale interaction mapping can report candidate BCL2-family edges, but this row lacks the focused validation and BH3-dependent mechanism needed to curate a PUMA-side apoptotic inhibitor activity. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: This is a high-throughput interactome edge that is not sufficient to define a PUMA molecular function. Reason: Large-scale interaction mapping can report candidate BCL2-family edges, but this row lacks the focused validation and BH3-dependent mechanism needed to curate a PUMA-side apoptotic inhibitor activity. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: This is a high-throughput interactome edge that is not sufficient to define a PUMA molecular function. Reason: Large-scale interaction mapping can report candidate BCL2-family edges, but this row lacks the focused validation and BH3-dependent mechanism needed to curate a PUMA-side apoptotic inhibitor activity. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: This is a high-throughput interactome edge that is not sufficient to define a PUMA molecular function. Reason: Large-scale interaction mapping can report candidate BCL2-family edges, but this row lacks the focused validation and BH3-dependent mechanism needed to curate a PUMA-side apoptotic inhibitor activity. |
| GO:0005739 mitochondrion | EXP PMID:11572983 Expression of bbc3, a pro-apoptotic BH3-only gene, is regula... | ACCEPT | Summary: PUMA has experimental mitochondrial localization that matches its apoptotic action at the BAX/BAK checkpoint. Reason: Founding low-throughput papers, sequence-family inference, and mitochondrial proteomics all place BBC3/PUMA at mitochondria when its BH3-only apoptotic activity is engaged. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: PUMA has experimental mitochondrial localization that matches its apoptotic action at the BAX/BAK checkpoint. Reason: Founding low-throughput papers, sequence-family inference, and mitochondrial proteomics all place BBC3/PUMA at mitochondria when its BH3-only apoptotic activity is engaged. |
| GO:0005739 mitochondrion | IDA PMID:11463391 PUMA induces the rapid apoptosis of colorectal cancer cells. | ACCEPT | Summary: PUMA has experimental mitochondrial localization that matches its apoptotic action at the BAX/BAK checkpoint. Reason: Founding low-throughput papers, sequence-family inference, and mitochondrial proteomics all place BBC3/PUMA at mitochondria when its BH3-only apoptotic activity is engaged. |
| GO:0005739 mitochondrion | IDA PMID:11463392 PUMA, a novel proapoptotic gene, is induced by p53. | ACCEPT | Summary: PUMA has experimental mitochondrial localization that matches its apoptotic action at the BAX/BAK checkpoint. Reason: Founding low-throughput papers, sequence-family inference, and mitochondrial proteomics all place BBC3/PUMA at mitochondria when its BH3-only apoptotic activity is engaged. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: PUMA has experimental mitochondrial localization that matches its apoptotic action at the BAX/BAK checkpoint. Reason: Founding low-throughput papers, sequence-family inference, and mitochondrial proteomics all place BBC3/PUMA at mitochondria when its BH3-only apoptotic activity is engaged. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-139914 | ACCEPT | Summary: Reactome places PUMA at the mitochondrial outer membrane while it translocates to mitochondria and inactivates pro-survival BCL2-family proteins. Reason: The outer mitochondrial membrane is the correct site for the BH3-only PUMA interactions that derepress or activate BAX/BAK-driven MOMP. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-508162 | ACCEPT | Summary: Reactome places PUMA at the mitochondrial outer membrane while it translocates to mitochondria and inactivates pro-survival BCL2-family proteins. Reason: The outer mitochondrial membrane is the correct site for the BH3-only PUMA interactions that derepress or activate BAX/BAK-driven MOMP. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-508163 | ACCEPT | Summary: Reactome places PUMA at the mitochondrial outer membrane while it translocates to mitochondria and inactivates pro-survival BCL2-family proteins. Reason: The outer mitochondrial membrane is the correct site for the BH3-only PUMA interactions that derepress or activate BAX/BAK-driven MOMP. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-139913 | KEEP AS NON CORE | Summary: This Reactome event is TP53-dependent transcription of the BBC3 gene, not evidence that PUMA protein acts in the cytosol. Reason: Cytosol is kept as a non-core location of PUMA on the other Reactome row for this term, and the claim is the same here. The Reactome event behind this row describes TP53-dependent transcription of the BBC3 gene; its product, newly made PUMA protein, is placed by Reactome in the cytosol, from where PUMA moves to mitochondria. The event is not itself a localization experiment, which limits this row's evidence but not the claim. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-139914 | KEEP AS NON CORE | Summary: A newly expressed or inactive cytosolic PUMA pool exists before mitochondrial translocation in some contexts. Reason: Reactome explicitly models PUMA movement from the cytosol to mitochondria, but the mitochondrial membrane-bound pool is the core apoptotic site of action. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-140221 | KEEP AS NON CORE | Summary: This Reactome event is E2F1-dependent transcription of the BBC3 gene; Reactome places the resulting PUMA protein in the cytosol. Reason: Cytosol is kept as a non-core location of PUMA on the other Reactome row for this term, and the claim is the same here. The Reactome event behind this row describes E2F1-dependent transcription of the BBC3 gene; its product, newly made PUMA protein, is placed by Reactome in the cytosol, from where PUMA moves to mitochondria. The event is not itself a localization experiment, which limits this row's evidence but not the claim. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9622667 | KEEP AS NON CORE | Summary: This Reactome event is FOXO-dependent transcription of the BBC3 gene; Reactome places the resulting PUMA protein in the cytosol. Reason: Cytosol is kept as a non-core location of PUMA on the other Reactome row for this term, and the claim is the same here. The Reactome event behind this row describes FOXO-dependent transcription of the BBC3 gene; its product, newly made PUMA protein, is placed by Reactome in the cytosol, from where PUMA moves to mitochondria. The event is not itself a localization experiment, which limits this row's evidence but not the claim. |
| GO:0006974 DNA damage response | IEA GO_REF:0000107 | MODIFY | Summary: PUMA mediates the apoptotic branch of the p53-class DNA-damage response rather than DNA-damage detection or repair. Reason: GO:0006974 is too broad for a BH3-only protein whose role is to execute p53-induced intrinsic apoptotic signaling downstream of genotoxic stress. Proposed replacements: intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator |
| GO:0006974 DNA damage response | ISS GO_REF:0000024 | MODIFY | Summary: PUMA mediates the apoptotic branch of the p53-class DNA-damage response rather than DNA-damage detection or repair. Reason: GO:0006974 is too broad for a BH3-only protein whose role is to execute p53-induced intrinsic apoptotic signaling downstream of genotoxic stress. Proposed replacements: intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator |
| GO:0008340 determination of adult lifespan | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Mouse Bbc3 loss changes organismal lifespan phenotypes through altered apoptosis, but adult lifespan determination is remote from the direct PUMA protein activity. Reason: This phenotype-level process should not be propagated as a BBC3 function when the direct conserved activity is BAX/BAK checkpoint regulation. |
| GO:0008340 determination of adult lifespan | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Mouse Bbc3 loss changes organismal lifespan phenotypes through altered apoptosis, but adult lifespan determination is remote from the direct PUMA protein activity. Reason: This phenotype-level process should not be propagated as a BBC3 function when the direct conserved activity is BAX/BAK checkpoint regulation. |
| GO:0031334 positive regulation of protein-containing complex assembly | IDA PMID:21041309 BH3 domains other than Bim and Bid can directly activate Bax... | MODIFY | Summary: The supported complex assembly is BAX/BAK oligomerization during apoptotic MOMP. Reason: GO:0031334 is too generic for Du et al.'s BH3-peptide activation of BAX/BAK pore assembly. |
| GO:0034976 response to endoplasmic reticulum stress | IDA PMID:22761832 CHOP potentially co-operates with FOXO3a in neuronal cells t... | MODIFY | Summary: ER stress induces PUMA so it can promote intrinsic apoptotic signaling downstream of the unfolded-protein response. Reason: PUMA is not a general ER-stress response factor; the supported role is positive regulation of ER-stress-induced intrinsic apoptosis. |
| GO:0034976 response to endoplasmic reticulum stress | IEA GO_REF:0000107 | MODIFY | Summary: ER stress induces PUMA so it can promote intrinsic apoptotic signaling downstream of the unfolded-protein response. Reason: PUMA is not a general ER-stress response factor; the supported role is positive regulation of ER-stress-induced intrinsic apoptosis. |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO captures PUMA as pro-apoptotic, but the direct process is BAX/BAK-dependent apoptotic MOMP. Reason: GO:0043065 is broader than the conserved BH3-only activity at the mitochondrial checkpoint. |
| GO:0043525 positive regulation of neuron apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: PUMA can promote apoptosis in neurons, especially downstream of ER stress. Reason: The cell-type-specific mouse transfer is compatible with PUMA biology, but neuron apoptosis is a contextual descendant of the core intrinsic-apoptosis function. |
| GO:0043525 positive regulation of neuron apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: PUMA can promote apoptosis in neurons, especially downstream of ER stress. Reason: The cell-type-specific mouse transfer is compatible with PUMA biology, but neuron apoptosis is a contextual descendant of the core intrinsic-apoptosis function. |
| GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress | IDA PMID:16407291 Endoplasmic reticulum stress-induced apoptosis: multiple pat... | ACCEPT | Summary: PUMA is induced during ER stress and is required for the downstream intrinsic apoptotic response in neuronal models. Reason: This term keeps the ER-stress input while placing PUMA on the intrinsic apoptotic branch rather than on generic UPR signaling. |
| GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress | IEA GO_REF:0000107 | ACCEPT | Summary: PUMA is induced during ER stress and is required for the downstream intrinsic apoptotic response in neuronal models. Reason: This term keeps the ER-stress input while placing PUMA on the intrinsic apoptotic branch rather than on generic UPR signaling. |
| GO:0070059 intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress | ISS GO_REF:0000024 | ACCEPT | Summary: PUMA is induced during ER stress and is required for the downstream intrinsic apoptotic response in neuronal models. Reason: This term keeps the ER-stress input while placing PUMA on the intrinsic apoptotic branch rather than on generic UPR signaling. |
| GO:0070245 positive regulation of thymocyte apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse Bbc3 promotes thymocyte apoptosis after genotoxic stress. Reason: The thymocyte row is a valid cell-type-specific context but is secondary to the shared mitochondrial BAX/BAK checkpoint function. |
| GO:0070245 positive regulation of thymocyte apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse Bbc3 promotes thymocyte apoptosis after genotoxic stress. Reason: The thymocyte row is a valid cell-type-specific context but is secondary to the shared mitochondrial BAX/BAK checkpoint function. |
| GO:0071456 cellular response to hypoxia | IEP PMID:20810912 Hypoxia downregulates p53 but induces apoptosis and enhances... | REMOVE | Summary: The hypoxic syncytiotrophoblast study does not support a positive PUMA cellular hypoxia response. Reason: The cached full text centers BAD and reports unchanged or slightly reduced puma mRNA under hypoxia, so this IEP row appears to over-read a negative expression result. |
| GO:0090200 positive regulation of release of cytochrome c from mitochondria | IEA GO_REF:0000002 | ACCEPT | Summary: Positive regulation of cytochrome-c release is the appropriate process-level summary of PUMA-driven BAX/BAK MOMP. Reason: This regulatory term correctly avoids assigning cytochrome-c release itself to PUMA. |
| GO:0090200 positive regulation of release of cytochrome c from mitochondria | IGI PMID:21041309 BH3 domains other than Bim and Bid can directly activate Bax... | ACCEPT | Summary: PUMA BH3 peptide promotes cytochrome-c release from mitochondria by derepressing and weakly activating BAX/BAK. Reason: The genetic-interaction evidence from Bid/Bim-deficient mitochondria supports a direct positive role in cytochrome-c release from mitochondria. |
| GO:0097193 intrinsic apoptotic signaling pathway | IDA PMID:17024184 Differential contribution of Puma and Noxa in dual regulatio... | ACCEPT | Summary: PUMA drives intrinsic apoptotic signaling by activating mitochondrial outer-membrane permeabilization. Reason: The IDA evidence places PUMA on the mitochondrial branch of apoptotic signaling rather than on a distant viability readout. |
| GO:0097193 intrinsic apoptotic signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: The PUMA family is a BH3-only family that promotes intrinsic apoptotic signaling. Reason: This InterPro2GO process is broad but still correct for the conserved activity of the PUMA family. |
| GO:0097194 execution phase of apoptosis | IDA PMID:11463391 PUMA induces the rapid apoptosis of colorectal cancer cells. | MODIFY | Summary: PUMA initiates intrinsic apoptotic signaling upstream of the caspase-dependent execution phase. Reason: The founding Yu et al. paper supports mitochondrial induction of apoptosis, but GO:0097194 is too far downstream for a BH3-only MOMP regulator. |
| GO:1902237 positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway | TAS PMID:22013210 The unfolded protein response: integrating stress signals th... | ACCEPT | Summary: PUMA can positively regulate ER-stress-induced intrinsic apoptotic signaling as the induced BH3-only effector. Reason: This term keeps PUMA downstream of ER-stress transcriptional signaling and within mitochondrial apoptosis. |
| GO:1903896 positive regulation of IRE1-mediated unfolded protein response | TAS PMID:22013210 The unfolded protein response: integrating stress signals th... | UNDECIDED | Summary: TAS annotation from a review of IRE1-alpha signalling. PUMA is induced downstream of the unfolded protein response; whether it also modulates IRE1-alpha, as the annotation states, cannot be checked without the review's full text. Reason: The term is a traceable author statement from a review of signalling through the stress sensor IRE1-alpha; only its abstract is available, so what the review says about PUMA cannot be checked. The same review is the source of the same term on BAX and BAK1, where it is kept as a non-core role, and BH3-only proteins have been reported to modulate IRE1-alpha signalling, so the claim cannot be dismissed as a simple confusion of downstream induction with upstream regulation. It is left undecided until the review can be read. |
| GO:2001244 positive regulation of intrinsic apoptotic signaling pathway | IMP PMID:17289999 Apoptosis initiated when BH3 ligands engage multiple Bcl-2 h... | MODIFY | Summary: PUMA acts at the mitochondrial BAX/BAK checkpoint to positively regulate intrinsic apoptotic signaling. Reason: GO:2001244 has the right sign and branch but is less precise than positive regulation of apoptotic MOMP for this BH3-only regulator. |
| GO:2001244 positive regulation of intrinsic apoptotic signaling pathway | IMP PMID:27031958 Nupr1/Chop signal axis is involved in mitochondrion-related ... | MODIFY | Summary: PUMA acts at the mitochondrial BAX/BAK checkpoint to positively regulate intrinsic apoptotic signaling. Reason: GO:2001244 has the right sign and branch but is less precise than positive regulation of apoptotic MOMP for this BH3-only regulator. |
| GO:2001244 positive regulation of intrinsic apoptotic signaling pathway | ISS GO_REF:0000024 | MODIFY | Summary: PUMA acts at the mitochondrial BAX/BAK checkpoint to positively regulate intrinsic apoptotic signaling. Reason: GO:2001244 has the right sign and branch but is less precise than positive regulation of apoptotic MOMP for this BH3-only regulator. |
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Download this section (compressed HTML)Q: Should GO add paired PUMA/BIM/BID-side molecular-function terms for BH3-only inhibition of pro-survival BCL2 proteins and direct activation of BAX/BAK, so these rows are not forced into GO:0005515 or the directionally wrong GO:0051434 BH3 domain binding term?
Q: Should Reactome-derived BBC3 transcription events be filtered so the expressed PUMA protein is not automatically annotated to the cytosol before any protein-level translocation or binding step occurs?
Experiment: For BBC3 interactions outside the BCL2-family core, map whether the partner alters PUMA mitochondrial translocation, pro-survival BCL2 groove occupancy, BAX/BAK activation, or MOMP directly before curating the edge as a PUMA molecular function.
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