CASP-9 (caspase 9, apoptosis-related cysteine peptidase)

Identity

Other names	APAF-3
	ICE-LAP6
	MCH6
HGNC	CASP9
Location	1p36.2

DNA/RNA

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.

Protein

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).

Mutations

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.

External links

	Nomenclature
HGNC	CASP9   1511
Entrez_Gene	CASP9  842  caspase 9, apoptosis-related cysteine peptidase
	Cards
Atlas	CASP9ID423ch1p36
GeneCards	CASP9
Ensembl	CASP9 [Search_View]   ENSG00000132906 [Gene_View]
Genatlas	CASP9
GeneLynx	CASP9
eGenome	CASP9
euGene	842
	Genomic and cartography
GoldenPath	CASP9  -  1p36.2   chr1:15691382-15723377 -  1p36.21   [Description]    (hg18-Mar_2006)
Ensembl	CASP9 - 1p36.21 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	CASP9
	Gene and transcription
Genbank	AB015653 [ ENTREZ ]
Genbank	AB020979 [ ENTREZ ]
Genbank	AB209147 [ ENTREZ ]
Genbank	AF093130 [ ENTREZ ]
Genbank	AF110376 [ ENTREZ ]
RefSeq	NM_001229 [ SRS ]    NM_001229 [ ENTREZ ]
RefSeq	NM_032996 [ SRS ]    NM_032996 [ ENTREZ ]
RefSeq	AC_000044 [ SRS ]    AC_000044 [ ENTREZ ]
RefSeq	AC_000133 [ SRS ]    AC_000133 [ ENTREZ ]
RefSeq	NC_000001 [ SRS ]    NC_000001 [ ENTREZ ]
RefSeq	NT_004873 [ SRS ]    NT_004873 [ ENTREZ ]
RefSeq	NW_001838564 [ SRS ]    NW_001838564 [ ENTREZ ]
RefSeq	NW_925794 [ SRS ]    NW_925794 [ ENTREZ ]
AceView	CASP9 AceView - NCBI
Unigene	Hs.329502 [ SRS ]    Hs.329502 [ NCBI ]     HS329502 [ spliceNest ]
Fast-db	7041 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P55211 [ SRS]    P55211 [ EXPASY ]     P55211 [ INTERPRO ]     P55211 [ UNIPROT ]
Prosite	PS50209 CARD [ SRS ]    PS50209 CARD [ Expasy ]
Prosite	PS01122 CASPASE_CYS [ SRS ]    PS01122 CASPASE_CYS [ Expasy ]
Prosite	PS01121 CASPASE_HIS [ SRS ]    PS01121 CASPASE_HIS [ Expasy ]
Prosite	PS50207 CASPASE_P10 [ SRS ]    PS50207 CASPASE_P10 [ Expasy ]
Prosite	PS50208 CASPASE_P20 [ SRS ]    PS50208 CASPASE_P20 [ Expasy ]
Interpro	IPR001315 CARD [ SRS ]    IPR001315 CARD [ EBI ]
Interpro	IPR017350 Caspase_IL-1_beta [ SRS ]    IPR017350 Caspase_IL-1_beta [ EBI ]
Interpro	IPR011029 DEATH_like [ SRS ]    IPR011029 DEATH_like [ EBI ]
Interpro	IPR011600 Pept_C14_cat [ SRS ]    IPR011600 Pept_C14_cat [ EBI ]
Interpro	IPR001309 Pept_C14_ICE_p20 [ SRS ]    IPR001309 Pept_C14_ICE_p20 [ EBI ]
Interpro	IPR016129 Pept_C14_ICE_p20_AS [ SRS ]    IPR016129 Pept_C14_ICE_p20_AS [ EBI ]
Interpro	IPR002138 Pept_C14_p10 [ SRS ]    IPR002138 Pept_C14_p10 [ EBI ]
Interpro	IPR002398 Pept_C14_p45 [ SRS ]    IPR002398 Pept_C14_p45 [ EBI ]
Interpro	IPR015917 Pept_C14_p45_core [ SRS ]    IPR015917 Pept_C14_p45_core [ EBI ]
CluSTr	P55211
Pfam	PF00619 CARD [ SRS ]    PF00619 CARD [ Sanger ]    pfam00619 [ NCBI-CDD ]
Pfam	PF00656 Peptidase_C14 [ SRS ]    PF00656 Peptidase_C14 [ Sanger ]    pfam00656 [ NCBI-CDD ]
Smart	SM00114 CARD [EMBL]
Smart	SM00115 CASc [EMBL]
Blocks	P55211
PDB	1JXQ [ SRS ]    1JXQ [ PdbSum ],   1JXQ [ IMB ]   1JXQ [ RSDB ]
PDB	1NW9 [ SRS ]    1NW9 [ PdbSum ],   1NW9 [ IMB ]   1NW9 [ RSDB ]
PDB	2AR9 [ SRS ]    2AR9 [ PdbSum ],   2AR9 [ IMB ]   2AR9 [ RSDB ]
PDB	3YGS [ SRS ]    3YGS [ PdbSum ],   3YGS [ IMB ]   3YGS [ RSDB ]
HPRD	03756
	Protein Interaction databases
DIP	P55211
IntAct	P55211
	Polymorphism : SNP, mutations, diseases
OMIM	602234    [ map ]
GENECLINICS	602234
SNP	CASP9 [dbSNP-NCBI]
SNP	NM_001229 [SNP-NCI]
SNP	NM_032996 [SNP-NCI]
SNP	CASP9 [GeneSNPs - Utah]  CASP9] [HGBASE - SRS]
HAPMAP	CASP9 [HAPMAP]
COSMIC	CASP9 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	CASP9
	General knowledge
Family Browser	CASP9 [UCSC Family Browser]
SOURCE	NM_001229
SOURCE	NM_032996
SMD	Hs.329502
SAGE	Hs.329502
Enzyme	3.4.22.62 [ Enzyme-Expasy ]   3.4.22.62 [ Enzyme-SRS ]   3.4.22.62 [ IntEnz-EBI ]   3.4.22.62 [ BRENDA ]   3.4.22.62 [ KEGG ]   3.4.22.62 [ WIT ]
GO	protein binding [Amigo]  protein binding
GO	protein binding [Amigo]  protein binding
GO	intracellular [Amigo]  intracellular
GO	cytosol [Amigo]  cytosol
GO	proteolysis [Amigo]  proteolysis
GO	apoptosis [Amigo]  apoptosis
GO	enzyme activator activity [Amigo]  enzyme activator activity
GO	cysteine-type peptidase activity [Amigo]  cysteine-type peptidase activity
GO	apoptotic program [Amigo]  apoptotic program
GO	caspase activation via cytochrome c [Amigo]  caspase activation via cytochrome c
GO	caspase activity [Amigo]  caspase activity
GO	caspase activity [Amigo]  caspase activity
GO	regulation of apoptosis [Amigo]  regulation of apoptosis
BIOCARTA	HIV-I Nef: negative effector of Fas and TNF    [Genes]
BIOCARTA	West Nile Virus    [Genes]
BIOCARTA	AKT Signaling Pathway    [Genes]
BIOCARTA	Caspase Cascade in Apoptosis    [Genes]
BIOCARTA	Apoptotic Signaling in Response to DNA Damage    [Genes]
BIOCARTA	D4-GDI Signaling Pathway    [Genes]
BIOCARTA	Induction of apoptosis through DR3 and DR4/5 Death Receptors    [Genes]
BIOCARTA	Stress Induction of HSP Regulation    [Genes]
BIOCARTA	Role of Mitochondria in Apoptotic Signaling    [Genes]
BIOCARTA	Ras Signaling Pathway    [Genes]
BIOCARTA	Trefoil Factors Initiate Mucosal Healing    [Genes]
KEGG	MAPK signaling pathway
KEGG	Apoptosis
KEGG	VEGF signaling pathway
KEGG	Colorectal cancer
PubGene	CASP9
TreeFam	CASP9
CTD	842 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	CASP9 Related clones (RZPD - Berlin)
	PubMed
PubMed	148 Pubmed reference(s) in LocusLink

Bibliography

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Identification of an alternative form of caspase-9 in human gastric cancer cell lines: a role of a caspase-9 variant in apoptosis resistance.

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Immunohistochemical profiling of caspase signaling pathways predicts clinical response to chemotherapy in primary nodal diffuse large B-cell lymphomas.

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Inhibition of caspase 9 and not caspase 8 mediated apoptosis may determine clinical response to chemotherapy in primary nodal diffuse large B-cell lymphomas.

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PMID 15876872

Antiangiogenic gene therapy: disruption of neovascular networks mediated by inducible caspase-9 delivered with a transcriptionally targeted adenoviral vector.

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Caspase 9 promoter polymorphisms and risk of primary lung cancer.

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PMID 16780893

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Contributor(s)

Written	12-2006	Sabrina Di Bartolomeo, Francesco Cecconi

Citation

This paper should be referenced as such :

Di Bartolomeo S, Cecconi F . CASP-9 (caspase 9, apoptosis-related cysteine peptidase). Atlas Genet Cytogenet Oncol Haematol. December 2006 . URL : http://AtlasGeneticsOncology.org/Genes/CASP9ID423ch1p36.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:12:43 2008