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CASP9 (caspase 9, apoptosis-related cysteine peptidase)

Written2006-12Sabrina Di Bartolomeo, Francesco Cecconi
Department of Biology, Via della Ricerca Scientifica, 00133, Rome, Italy

(Note : for Links provided by Atlas : click)


Alias (NCBI)CASP-9 (caspase 9, apoptosis-related cysteine peptidase)
HGNC Alias symbMCH6
HGNC Alias nameprotein phosphatase 1, regulatory subunit 56
HGNC Previous namecaspase 9, apoptosis-related cysteine protease
 caspase 9, apoptosis-related cysteine peptidase
LocusID (NCBI) 842
Atlas_Id 423
Location 1p36.21  [Link to chromosome band 1p36]
Location_base_pair Starts at 15491401 and ends at 15524790 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping CASP9.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)


Description The human caspase-9 gene contains 9 exons and 8 introns and was predicted to span over approximately 35 kb of the genomic DNA.
Transcription Three mRNA isoforms have been identified in Homo sapiens.
Caspase-9S, also classified as caspase-9b or caspase-9beta, is a small variant of caspase-9 lacking exons 3-6, which contain the catalytic domain. Caspase-9S functions as an endogenous dominant-negative isoform of full-length caspase-9 by binding to the Apaf-1 protein thus hampering its binding and processing of the full-length procaspase-9.
Recently, it has been cloned and characterized a novel caspase-9 splice variant, named caspase9-gamma. Caspase9-gamma is generated from an alternative splicing of the fourth exon of caspase-9 gene, that results in a 58 nucleotide-long insertion, absent in caspase-9 full length. As the inserted fragment introduces a stop codon, the resulting RNA sequence is prematurely terminated and translated in a 154 aminoacids protein corresponding to only the CARD domain of the caspase-9 full length. Caspase9-gamma does not contain small and large catalytic subunits and cannot promote apoptosis, but like caspase-S, it can function as an apoptosis inhibitor by interferring with the CARD-CARD interaction between procaspase-9 and Apaf-1.


Description Like for other caspase genes, caspase-9 mRNA is translated in a precursor protein, the procaspase, that is subsequently converted to the active enzyme. The procaspase-9 consists of 416 amino acids corresponding to a molecular weight of 46281 Da. Cleavages at Asp315 and Asp330 by granzyme B and CPP32 (caspase-3), respectively, generate two active peptides. The active caspase-9 is, in fact, constituted by an heterodimer of a 35kDa (p35) and a 10 kDa (p10) subunit. It belongs to the peptidase C14 family and contains three major domains: a prodomain (in which a CARD domain is located), a large subunit catalytic domain (LSCD) and a small subunit catalytic domain (SSCD).
Expression Caspase-9 expression is ubiquitous, with highest expression in the heart and a moderate expression in liver, skeletal muscle, and pancreas.
Localisation Mainly cytosolic, but both proenzyme and active caspase-9 have been also observed in the mitochondria and in the nucleus.
Function Caspase-9 is a member of the cysteine aspartic acid protease, or caspase, family. The procaspase-9 is activated in apoptotic conditions and it is involved in the activation of the caspase cascade responsible for apoptosis execution. The procaspase-9 and Apaf-1 interact each other through their CARD domains generating, in presence of cytochrome c and ATP, the protein complex named "apoptosome". The latter one, in turn, cleaves and activates the effector caspases such the caspase-3.
Caspase-9 plays an essential role in apoptosis during normal development. The majority of homozygous CASP-9 null mice die perinatally with an enlarged and malformed cerebrum caused by a reduced apoptosis during brain development.
Homology CASP9 (Canis familiaris, Pan troglodytes, Gallus gallus), Casp9 (Rattus norvegicus, Mus musculus), Casp9-A (Xenopous Laevis), Dr.16035 (Danio Rerio).


Germinal Not known in Homo sapiens
Somatic Three different somatic mutations have been detected in two colorectal carcinomas and in one gastric carcinoma among 353 cancer specimen analyzed, including 180 gastric, 104 colorectal and 69 lung adenocarcinomas. However, all these mutations were silent mutation, thus not contributing to the pathogenesis of these cancers.

Implicated in

Entity Lung cancer
Cytogenetics CASP-9 promoter polymorphisms influence the promoter activity and are associated with the risk of developing lung cancer.
Oncogenesis It has been examined the association of four CASP-9 promoter polymorphisms with the risk of lung cancer in a Korean population comprising 432 lung cancer patients and 432 healthy controls. The -1263 GG genotype was associated with a significantly decreased risk of lung cancer compared with -1263 AA or combined -1263 AA + AG. Moreover, individuals with at least one -712T allele had a significantly increased risk of lung cancer compared with those carrying the -712 CC genotype. In brief, the polymorphisms that result in an higher promoter activity seem to be associated with a decreased risk to develop lung cancer. Polymorphisms in CASP-9 promoter can then be useful markers for determining genetic susceptibility to this cancer. However, the association between CASP-9 polymorphisms and risk of lung cancer seem to be influenced by tobacco smoking, no association being present in never-smoker patients. Moreover, as polymorphisms can show ethnic variations, the observations should be extended to diverse ethnic groups.
Disease Colon cancer
Oncogenesis Caspase-9 was shown to be downregulated in colon cancer samples in comparison with normal mucosa tissues. Immunohistochemical analysis reveals that the expression of caspase-9 is variable in the healthy enterocytes. However, in the enterocytic component of 12 among 26 cancer samples analyzed, a decrease in caspase-9 immunostaining intensity has been observed: a profile similar, but to a smaller extent, to that observed for caspase 7.
Entity Head and neck squamous cell carcinoma
Oncogenesis In a certain type of head and neck squamous cell carcinoma cells (HNSCCs), the inhibition of caspase-9 activity and Apaf-1 expression may represent a mechanism of acquired cisplatin resistance. It has been reported that cisplatin induced caspase-9 activation and apoptosis in cisplatin-sensitive HNSCCs in vitro. On the contrary, the cisplatin-resistant HNSCCs analyzed were not able to activate caspase-9 following cisplatin treatment, thus not responding to the therapy.
Entity Testicular germ cell cancer
Oncogenesis Similarly to head and neck squamous cell carcinama cells, failure of activation of caspase-9 induces cisplatin resistance in testicular cancer cells in vitro. Testicular germ cell cancer is a tumor highly responsive to cisplatin-based chemotherpy, but in a few cases a phenomenon of chemoresistence can occour leading to an unfavourable prognosis. In in vitro experiments, it has been shown that a cisplatin-resistant human testicular germ cell cancer cell line (1411HP) failed to activate caspase-9 and apoptosis after cisplatin treatment in comparison with two cisplatin-sensitive human testicular germ cell cancer cell line (2102EP and H12.1). In the resistant cell line, however, it was possible induce a caspase-9 independent apoptosis using a 3.3-fold higher cisplatin dose.
Entity Nodal diffuse large B-cell lymphoma
Oncogenesis By using biopsy specimens of primary diffuse large B-cell lymphoma (DLBCL) it has been demonstrated that a cellular profile consistent with inhibition of the caspase-9 pathway is associated with poor response to chemotherapy and fatal outcome. On the contrary, a cellular profile consistent with caspase-8 pathway inhibition is associated with an excellent response to chemotherapy. Identifying the functional status of caspase-9 and caspase-8 in patients may have implications for the outcome prediction and for development of alternative therapeutics strategies.
Entity Gastric cancer
Oncogenesis Seven cell lines derived from human gastric cancers were used to investigate the involvement of caspases in chemoresistance mechanisms. Among those examined, the cell line most resistant to apoptotic stimuli expressed the highest levels of the caspase-9 isoform beta, thus confirming the role of caspase-9 in promoting apoptosis in treated cancer cells.

To be noted

Caspase-9 molecular manipulation could be useful for T-cell therapy and for antiangiogenic gene therapy. It has been observed that the local delivery of an inducible caspase-9 resulted in endothelial cell apoptosis and local ablation of vicrovessels in a mouse model of human angiogenesis. Adenoviral vectors containing inducible forms of caspase-9 could be used as antiangiogenic drugs for treatment of angiogenesis-dependent diseases, as, in example, cancer.


Genomic organization of the human caspase-9 gene on Chromosome 1p36. 1-p36.3.
Hadano S, Nasir J, Nichol K, Rasper DM, Vaillancourt JP, Sherer SW, Beatty BG, Ikeda JE, Nicholson DW, Hayden MR
Mammalian genome : official journal of the International Mammalian Genome Society. 1999 ; 10 (7) : 757-760.
PMID 10384055
Identification of an alternative form of caspase-9 in human gastric cancer cell lines: a role of a caspase-9 variant in apoptosis resistance.
Izawa M, Mori T, Satoh T, Teramachi K, Sairenji T
Apoptosis : an international journal on programmed cell death. 1999 ; 4 (5) : 321-325.
PMID 14634335
Caspase-9 regulation: an update.
Johnson CR, Jarvis WD
Apoptosis : an international journal on programmed cell death. 2004 ; 9 (4) : 423-427.
PMID 15192324
Kuida K
The international journal of biochemistry & cell biology. 2000 ; 32 (2) : 121-124.
PMID 10687948
Inhibition of caspase-9 activity and Apaf-1 expression in cisplatin-resistant head and neck squamous cell carcinoma cells.
Kuwahara D, Tsutsumi K, Oyake D, Ohta T, Nishikawa H, Koizuka I
Auris, nasus, larynx. 2003 ; 30 Suppl : S85-S88.
PMID 12543167
Failure of activation of caspase-9 induces a higher threshold for apoptosis and cisplatin resistance in testicular cancer.
Mueller T, Voigt W, Simon H, Fruehauf A, Bulankin A, Grothey A, Schmoll HJ
Cancer research. 2003 ; 63 (2) : 513-521.
PMID 12543810
Immunohistochemical profiling of caspase signaling pathways predicts clinical response to chemotherapy in primary nodal diffuse large B-cell lymphomas.
Muris JJ, Cillessen SA, Vos W, van Houdt IS, Kummer JA, van Krieken JH, Jiwa NM, Jansen PM, Kluin-Nelemans HC, Ossenkoppele GJ, Gundy C, Meijer CJ, Oudejans JJ
Blood. 2005 ; 105 (7) : 2916-2923.
PMID 15576477
Inhibition of caspase 9 and not caspase 8 mediated apoptosis may determine clinical response to chemotherapy in primary nodal diffuse large B-cell lymphomas.
Oudejans JJ, Muris JJ, Meijer CJ
Cell cycle (Georgetown, Tex.). 2005 ; 4 (4) : 526-528.
PMID 15876872
Caspase 7 downregulation as an immunohistochemical marker of colonic carcinoma.
Palmerini F, Devilard E, Jarry A, Birg F, Xerri L
Human pathology. 2001 ; 32 (5) : 461-467.
PMID 11381362
Caspase 9 promoter polymorphisms and risk of primary lung cancer.
Park JY, Park JM, Jang JS, Choi JE, Kim KM, Cha SI, Kim CH, Kang YM, Lee WK, Kam S, Park RW, Kim IS, Lee JT, Jung TH
Human molecular genetics. 2006 ; 15 (12) : 1963-1971.
PMID 16687442
Caspases and cancer: mechanisms of inactivation and new treatment modalities.
Philchenkov A, Zavelevich M, Kroczak TJ, Los M
Experimental oncology. 2004 ; 26 (2) : 82-97.
PMID 15273659
Nuclear localization of procaspase-9 and processing by a caspase-3-like activity in mammary epithelial cells.
Ritter PM, Marti A, Blanc C, Baltzer A, Krajewski S, Reed JC, Jaggi R
European journal of cell biology. 2000 ; 79 (5) : 358-364.
PMID 10887967
A caspase-9 variant missing the catalytic site is an endogenous inhibitor of apoptosis.
Seol DW, Billiar TR
The Journal of biological chemistry. 1999 ; 274 (4) : 2072-2076.
PMID 9890966
Antiangiogenic gene therapy: disruption of neovascular networks mediated by inducible caspase-9 delivered with a transcriptionally targeted adenoviral vector.
Song W, Sun Q, Dong Z, Spencer DM, Nez G, Nör JE
Gene therapy. 2005 ; 12 (4) : 320-329.
PMID 15616606
Mutational analysis of proapoptotic caspase-9 gene in common human carcinomas.
Soung YH, Lee JW, Kim SY, Park WS, Nam SW, Lee JY, Yoo NJ, Lee SH
APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. 2006 ; 114 (4) : 292-297.
PMID 16689829
Identification of an endogenous dominant-negative short isoform of caspase-9 that can regulate apoptosis.
Srinivasula SM, Ahmad M, Guo Y, Zhan Y, Lazebnik Y, Fernandes-Alnemri T, Alnemri ES
Cancer research. 1999 ; 59 (5) : 999-1002.
PMID 10070954
Mitochondrial release of caspase-2 and -9 during the apoptotic process.
Susin SA, Lorenzo HK, Zamzami N, Marzo I, Brenner C, Larochette N, Prévost MC, Alzari PM, Kroemer G
The Journal of experimental medicine. 1999 ; 189 (2) : 381-394.
PMID 9892620
Cloning of a novel human caspase-9 splice variant containing only the CARD domain.
Wang P, Shi T, Ma D
Life sciences. 2006 ; 79 (10) : 934-940.
PMID 16780893


This paper should be referenced as such :
Cecconi, F ; Di Bartolomeo, S
CASP-9 (caspase 9, apoptosis-related cysteine peptidase)
Atlas Genet Cytogenet Oncol Haematol. 2007;11(2):90-92.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(1;1)(p36;q21) in Non Hodgkin Lymphoma

External links

HGNC (Hugo)CASP9   1511
Entrez_Gene (NCBI)CASP9    caspase 9
AliasesAPAF-3; APAF3; ICE-LAP6; MCH6; 
GeneCards (Weizmann)CASP9
Ensembl hg19 (Hinxton)ENSG00000132906 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000132906 [Gene_View]  ENSG00000132906 [Sequence]  chr1:15491401-15524790 [Contig_View]  CASP9 [Vega]
ICGC DataPortalENSG00000132906
TCGA cBioPortalCASP9
Genatlas (Paris)CASP9
SOURCE (Princeton)CASP9
Genetics Home Reference (NIH)CASP9
Genomic and cartography
GoldenPath hg38 (UCSC)CASP9  -     chr1:15491401-15524790 -  1p36.21   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CASP9  -     1p36.21   [Description]    (hg19-Feb_2009)
GoldenPathCASP9 - 1p36.21 [CytoView hg19]  CASP9 - 1p36.21 [CytoView hg38]
Genome Data Viewer NCBICASP9 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AA534393 AB015653 AB020979 AB209147 AF093130
RefSeq transcript (Entrez)NM_001229 NM_001278054 NM_032996
Consensus coding sequences : CCDS (NCBI)CASP9
Gene ExpressionCASP9 [ NCBI-GEO ]   CASP9 [ EBI - ARRAY_EXPRESS ]   CASP9 [ SEEK ]   CASP9 [ MEM ]
Gene Expression Viewer (FireBrowse)CASP9 [ Firebrowse - Broad ]
GenevisibleExpression of CASP9 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)842
GTEX Portal (Tissue expression)CASP9
Human Protein AtlasENSG00000132906-CASP9 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)CASP9
Human Protein Atlas [tissue]ENSG00000132906-CASP9 [tissue]
Protein Interaction databases
Complex Portal (EBI) CPX-991 Caspase-9 complex
CPX-991 Caspase-9 complex
CPX-3762 Apoptosome
CPX-3762 Apoptosome
CPX-3762 Apoptosome
CPX-3762 Apoptosome
Ontologies - Pathways
PubMed435 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:14:09 CEST 2021

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