Affinage

CASP7

Caspase-7 · UniProt P55210

Length
303 aa
Mass
34.3 kDa
Annotated
2026-04-28
47 papers in source corpus 8 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CASP7 is an executioner cysteine protease that functions as a central effector in apoptosis, cleaving key cellular substrates including PARP and lamin B1 downstream of death receptor, p53, and cytotoxic lymphocyte signaling pathways (PMID:8576161, PMID:9078237). Synthesized as a cytoplasmic 35-kDa proenzyme, CASP7 is proteolytically activated by initiator caspases (CASP3, CASP10) and granzyme B through cleavage at conserved aspartate sites to yield active large (p20) and small (p12) subunits; notably, CASP3 activates CASP7 but not vice versa, and the p17 subunit of CASP3 can form a functional heteromeric complex with the CASP7 p12 subunit (PMID:8521391, PMID:8755496, PMID:8631895). CASP7 enzymatic activity is directly inhibited by XIAP through its linker-BIR2 domain binding at a site involving Asp93 on CASP7, and disruption of this interaction selectively kills CASP3-deficient cancer cells (PMID:40533441). CASP7 expression is post-transcriptionally regulated by miR-212-5p, which targets its 3′UTR within a lncfos/miR-212-5p/CASP7 axis that modulates neuronal apoptosis during ischemic injury (PMID:36715920).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1995 High

    Identification of CASP7 as a DEVD-cleaving executioner caspase resolved the question of whether additional CPP32-like proteases exist and established that CASP7 autocatalytically processes into p20/p12 subunits with PARP-cleaving activity indistinguishable from CASP3.

    Evidence Recombinant expression in bacteria, in vitro protease activity assays with DEVD-AMC and PARP substrates, SDS-PAGE of processing products

    PMID:8521391

    Open questions at the time
    • Whether CASP7 has unique substrates distinct from CASP3 remained unknown
    • In vivo role versus CASP3 not addressed
    • Crystal structure not yet available
  2. 1995 High

    Demonstration that CASP3 cleaves proCASP7 but not vice versa, and that CASP3-p17/CASP7-p12 heteromers are enzymatically active, established the hierarchical and cooperative relationship between the two executioner caspases.

    Evidence Recombinant cross-cleavage assays and heteromeric complex reconstitution in Sf9 cells with apoptosis readout

    PMID:8521391

    Open questions at the time
    • Physiological relevance of CASP3/CASP7 heteromers in cells not demonstrated
    • Whether other caspases can also activate CASP7 was unknown
  3. 1996 High

    Mapping of granzyme B and initiator caspase (CASP10/Mch4) cleavage sites on proCASP7 placed CASP7 firmly in both the CTL/NK cytotoxicity and death-receptor apoptotic cascades, answering how CASP7 is activated upstream.

    Evidence In vitro reconstitution with purified granzyme B and recombinant CASP10; N-terminal sequencing of cleavage products; cell-based assay with granzyme B plus perforin in Jurkat cells

    PMID:8576161 PMID:8631895 PMID:8755496 PMID:8805307

    Open questions at the time
    • Whether CASP8 or CASP9 directly activate CASP7 was not tested
    • Relative contribution of granzyme B versus caspase-mediated activation in vivo unresolved
  4. 1996 High

    Demonstration that endogenous CASP7 is processed during Fas- and TNF-induced apoptosis, and that its overexpression induces apoptosis, confirmed CASP7 as a physiological effector caspase rather than a biochemical curiosity.

    Evidence Western blot of endogenous CASP7 processing in Fas/TNF-stimulated cells; overexpression of truncated CASP7 in MCF7 cells; subcellular fractionation showing cytoplasmic localization

    PMID:8576161

    Open questions at the time
    • Non-apoptotic functions of CASP7 not explored
    • Tissue-specific roles not addressed
  5. 1997 Medium

    Placing CASP7 activation downstream of p53 induction expanded the known apoptotic contexts of CASP7 beyond death receptors and granzyme B to include intrinsic/genotoxic stress pathways.

    Evidence Temperature-sensitive p53 cell line with Western blot detection of CASP7 processing and PARP/lamin B1 cleavage

    PMID:9078237

    Open questions at the time
    • Whether p53-mediated activation proceeds through mitochondrial caspase-9 or another route not determined
    • Single cell system used
  6. 2023 Medium

    Identification of miR-212-5p as a direct post-transcriptional repressor of CASP7 via its 3′UTR, within a lncfos/miR-212-5p/CASP7 axis, revealed a non-caspase regulatory layer controlling CASP7 expression in neuronal ischemia.

    Evidence Dual-luciferase reporter assay validating miR-212-5p binding to CASP7 3′UTR; in vivo agomir/antagomir experiments in rat MCAO stroke model

    PMID:36715920

    Open questions at the time
    • Whether this axis operates outside the CNS is unknown
    • Endogenous CASP7 protein levels not confirmed by Western blot in all conditions
    • Single lab finding
  7. 2025 High

    Structural and pharmacological dissection of the XIAP-CASP7 inhibitory interaction revealed that XIAP linker-BIR2 engages CASP7 at Asp93, and that a small molecule disrupting this interface selectively reactivates CASP7 in CASP3-deficient cancers, establishing CASP7 as a druggable apoptotic effector.

    Evidence Virtual screening, in vitro binding assays, Asp93 mutagenesis abolishing inhibitor effect, MCF-7 and TNBC cell viability, in vivo xenograft

    PMID:40533441

    Open questions at the time
    • Full structural model of the CASP7-inhibitor-XIAP ternary complex not solved
    • Whether other IAPs regulate CASP7 similarly is untested
    • Long-term in vivo safety of XIAP-CASP7 disruption not evaluated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The non-apoptotic functions of CASP7 (e.g., in inflammation, differentiation, or tissue remodeling) and its complete endogenous substrate repertoire distinct from CASP3 remain uncharacterized in the direct mechanistic literature.
  • No systematic substrate profiling distinguishing CASP7 from CASP3 in cells
  • Non-apoptotic roles not addressed by any discovery in the timeline
  • Physiological relevance of CASP3/CASP7 heteromeric complexes in vivo remains untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-5357801 Programmed Cell Death 8 R-HSA-168256 Immune System 3
Partners
CASP10CASP3GZMBXIAP

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 CASP7 (Mch3/CMH-1) is synthesized as a proenzyme that undergoes autocatalytic/autoactivation processing into two subunits (p20 and p12); the active enzyme cleaves PARP and has substrate specificity toward DEVD-AMC similar to CPP32/CASP3. Bacterial recombinant expression, in vitro protease activity assay, autocatalytic processing demonstrated by SDS-PAGE Cancer research High 8521391
1995 CPP32/CASP3 can cleave proCASP7 (proMch3α) to generate active CASP7, but CASP7 cannot efficiently cleave proCASP3, establishing a unidirectional activation relationship; additionally, the p17 subunit of CASP3 can form an active heteromeric complex with the p12 subunit of CASP7. Recombinant protein co-expression in Sf9 cells, cross-cleavage assay, apoptosis induction assay Cancer research High 8521391
1996 Granzyme B directly cleaves and activates CASP7 (ICE-LAP3/Mch3/CMH-1) at Asp198-Ser199 (between p20 and p12 subunits); autocatalytic cleavage at the prosequence site (Asp23-Ala24) is not required for CASP7 activity in vitro. In vitro cleavage assay with purified granzyme B and recombinant CMH-1/CASP7; site-specific cleavage mapped by N-terminal sequencing The Journal of biological chemistry High 8576161 8631895 8805307
1996 CASP7 (ICE-LAP3) is activated during Fas- and TNF-induced apoptosis; endogenous CASP7 is processed to its subunit forms upon receipt of a death stimulus, and overexpression of a truncated (pro-domain-deleted) form induces apoptosis in MCF7 cells. Western blot of endogenous CASP7 processing; overexpression of truncated CASP7 in MCF7 cells with apoptosis readout The Journal of biological chemistry High 8576161
1996 CASP7 (ICE-LAP3) is localized to the cytoplasm as a 35-kDa proenzyme in multiple tissues and cell lines. Subcellular fractionation and immunocytochemistry The Journal of biological chemistry Medium 8576161
1996 Granzyme B activates endogenous CASP7 (ICE-LAP3) in Jurkat T cells treated with granzyme B plus sublytic perforin, preceding apoptosis, placing CASP7 downstream of granzyme B in CTL/NK-mediated cytotoxicity. Cell-based apoptosis assay with granzyme B and perforin; Western blot of endogenous CASP7 processing Current biology : CB High 8805307
1996 CASP7 (Mch3) is activated by Mch4/CASP10 in vitro; Mch4 cleaves proMch3 at a conserved IXXD-S sequence to produce the large and small subunits of active CASP7, establishing CASP7 as a downstream target of initiator caspase Mch4. In vitro cleavage assay with recombinant Mch4 and recombinant proCASP7; SDS-PAGE analysis of processing Proceedings of the National Academy of Sciences of the United States of America High 8755496
1996 CASP7 (Mch3) is cleaved by granzyme B at a conserved IXXD-A processing sequence, analogous to CPP32 processing, placing CASP7 in the granzyme B apoptotic pathway. In vitro cleavage assay with recombinant granzyme B and proMch3/proCASP7 Proceedings of the National Academy of Sciences of the United States of America High 8755496
1997 CASP7 (Mch3α/CPP32) activation occurs downstream of p53-induced apoptosis, accompanied by cleavage of PARP and lamin B1, placing CASP7 as an effector protease in the p53 apoptotic pathway. Temperature-sensitive p53 cell line (LTR6); Western blot of CASP7 processing and substrate cleavage The Biochemical journal Medium 9078237
2025 XIAP binds CASP7 via its linker-BIR2 domain to inhibit CASP7; a small molecule inhibitor (643943) binds CASP7 at Asp93, releases the XIAP linker-BIR2 domain, and reactivates CASP7, selectively killing CASP3-deficient (CASP3/DR) cancer cells; mutation of Asp93 on CASP7 abolishes inhibitor cytotoxicity. Virtual screening, in vitro binding assay, site-directed mutagenesis (Asp93 substitution), cell viability assay in MCF-7 and TNBC lines, in vivo xenograft Cell death & disease High 40533441
2023 miR-212-5p directly targets the CASP7 3'UTR (validated by dual-luciferase assay), and lncfos suppresses miR-212-5p, forming a lncfos/miR-212-5p/CASP7 regulatory axis; upregulation of miR-212-5p reduces CASP7 expression and neuronal apoptosis in a rat MCAO ischemic stroke model. Dual-luciferase reporter assay for miR-212-5p binding to CASP7 3'UTR; intracerebroventricular injection of miR-212-5p agomir/antagomir and sh-fos in rat MCAO model; qRT-PCR, infarct volume, neurological scoring Molecular neurobiology Medium 36715920

Source papers

Stage 0 corpus · 47 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proceedings of the National Academy of Sciences of the United States of America 672 8755496
1995 Mch3, a novel human apoptotic cysteine protease highly related to CPP32. Cancer research 380 8521391
2007 Template-based modeling and free modeling by I-TASSER in CASP7. Proteins 338 17894355
1996 ICE-LAP3, a novel mammalian homologue of the Caenorhabditis elegans cell death protein Ced-3 is activated during Fas- and tumor necrosis factor-induced apoptosis. The Journal of biological chemistry 329 8576161
2007 Structure prediction for CASP7 targets using extensive all-atom refinement with Rosetta@home. Proteins 119 17894356
2007 Assessment of CASP7 predictions for template-based modeling targets. Proteins 118 17894352
1996 Cytotoxic T-cell-derived granzyme B activates the apoptotic protease ICE-LAP3. Current biology : CB 91 8805307
2007 Assessment of disorder predictions in CASP7. Proteins 83 17680688
2007 Automated server predictions in CASP7. Proteins 81 17894354
2007 Assessment of CASP7 structure predictions for template free targets. Proteins 75 17894330
2007 Prediction of global and local model quality in CASP7 using Pcons and ProQ. Proteins 68 17894353
1996 Processing and activation of CMH-1 by granzyme B. The Journal of biological chemistry 58 8631895
2007 Assessment of intramolecular contact predictions for CASP7. Proteins 55 17671976
2007 Analysis of TASSER-based CASP7 protein structure prediction results. Proteins 48 17705276
2007 Assessment of predictions submitted for the CASP7 function prediction category. Proteins 41 17654548
2019 A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association 35 30503768
1997 Identification and mapping of Casp7, a cysteine protease resembling CPP32 beta, interleukin-1 beta converting enzyme, and CED-3. Genomics 35 9070923
2007 Assessment of predictions submitted for the CASP7 domain prediction category. Proteins 34 17680686
2007 Evaluation of 3D-Jury on CASP7 models. BMC bioinformatics 26 17711571
2015 Genome-wide haplotype association study identify TNFRSF1A, CASP7, LRP1B, CDH1 and TG genes associated with Alzheimer's disease in Caribbean Hispanic individuals. Oncotarget 24 26621834
1997 Activation of CPP32 and Mch3 alpha in wild-type p53-induced apoptosis. The Biochemical journal 24 9078237
2018 Detection of Plasmid-Mediated β-Lactamase Genes and Emergence of a Novel AmpC (CMH-1) in Enterobacter cloacae at a Medical Center in Southern Taiwan. Journal of clinical medicine 23 30577544
2016 A loss of function variant in CASP7 protects against Alzheimer's disease in homozygous APOE ε4 allele carriers. BMC genomics 22 27358062
1996 Chromosomal localization of the human genes, CPP32, Mch2, Mch3, and Ich-1, involved in cellular apoptosis. Biochemical and biophysical research communications 22 8780721
2013 HuGE systematic review and meta-analysis demonstrate association of CASP-3 and CASP-7 genetic polymorphisms with cancer risk. Genetics and molecular research : GMR 20 23765963
1998 Cloning, sequencing, and expression of an endoglucanase gene from the rumen anaerobic fungus Neocallimastix frontalis MCH3. Bioscience, biotechnology, and biochemistry 20 9805384
1995 Effects of live Saccharomyces cerevisiae cells on zoospore germination, growth, and cellulolytic activity of the rumen anaerobic fungus, Neocallimastix frontalis MCH3. Current microbiology 20 7549764
2007 Domain definition and target classification for CASP7. Proteins 18 17654725
2017 Genetic Susceptibility in Acute Pancreatitis: Genotyping of GSTM1, GSTT1, GSTP1, CASP7, CASP8, CASP9, CASP10, LTA, TNFRSF1B, and TP53 Gene Variants. Pancreas 14 27984487
2015 CASP7 variants modify susceptibility to cervical cancer in Chinese women. Scientific reports 13 25784056
2013 Potentially functional polymorphisms in the CASP7 gene contribute to gastric adenocarcinoma susceptibility in an eastern Chinese population. PloS one 11 24040159
2012 Association between CASP7 and CASP14 genetic polymorphisms and the risk of childhood leukemia. Human immunology 11 22548721
2008 Genetic and expression analysis of CASP7 gene in a European Caucasian population with rheumatoid arthritis. The Journal of rheumatology 10 18785314
2019 Association of genetic polymorphisms in CASP7 with risk of ischaemic stroke. Scientific reports 7 31819117
2012 Association of CASP7 polymorphisms and survival of patients with non-small cell lung cancer with platinum-based chemotherapy treatment. Chest 7 22441531
1996 Chromosomal mapping of cell death proteases CPP32, MCH2, and MCH3. Genomics 7 8812467
2023 lncfos/miR-212-5p/CASP7 Axis-Regulated miR-212-5p Protects the Brain Against Ischemic Damage. Molecular neurobiology 6 36715920
2020 The Relevance of SNPs at 3'UTR Region of CASP7 and miR-371b-5p Associated Diseases: A Computational Analysis. Cell biochemistry and biophysics 6 32951155
2023 TLR2 and CASP7 as the biomarkers associated with non-alcoholic fatty liver disease and chronic kidney disease. Biochemical and biophysical research communications 5 37209562
2024 The Nephroprotective Activity of Boesenbergia Rotunda Rhizome by Reducing Creatinine, Urea Nitrogen, Glutamic Pyruvic Transaminase, and Malondialdehyde Levels in the Blood and Attenuating the Expression of Havcr1 (KIM-1), Lcn2 (NGAL), Casp3, and Casp7 Genes in the Kidney Cortex of Cisplatin-Induced Sprague-Dawley Rats. Journal of experimental pharmacology 4 38736464
2021 Role of CASP7 polymorphisms in noise-induced hearing loss risk in Han Chinese population. Scientific reports 4 33469117
2011 Unsupervised Integration of Multiple Protein Disorder Predictors: The Method and Evaluation on CASP7, CASP8 and CASP9 Data. Proteome science 3 22166115
2019 [Expression of Cell Cycle, Oxidative Stress, and Apoptosis Related Genes Chek1, Hmox1, Casp7 in Rat Liver Exposed to Carbon Tetrachloride]. Molekuliarnaia biologiia 2 30895955
2025 Blocking XIAP:CASP7-p19 selectively induces apoptosis of CASP3/DR malignancies by a novel reversible small molecule. Cell death & disease 1 40533441
2026 Fufang Baizhi tincture protects melanocytes from oxidative stress by targeting CASP7-mediated apoptosis and EP300-associated transcriptional regulation. Journal of ethnopharmacology 0 41713816
2025 The complete genome sequence of the Pediococcus siamensis type strain MCH3-2T (= JCM 13997T = LMG 24279T) Tanasupawat et al. 2007, 1372VP. Microbiology resource announcements 0 40862359
2024 Identification and Characterization of a Novel CCDC6::CASP7 Gene Rearrangement in an Advanced Colorectal Cancer Patient: A Case Report. International journal of molecular sciences 0 39684377