Disease relevance of CASP9

• Analyses of apoptotic regulators CASP9 and DFFA at 1P36.2, reveal rare allele variants in human neuroblastoma tumours [1].
• Methylation and deletion of Apaf-1 and CASP8 results in the loss of their expression in melanoma and neuroblastoma, respectively, while CASP9 localization to 1p36.1 suggests it is a good candidate tumor suppressor [2].
• The CASP-9 genotypes were determined in 432 lung cancer patients and 432 healthy controls that were frequency-matched for age and gender [3].
• We have previously reported that cisplatin induces caspase-9 (Casp9) activation in head and neck squamous cell carcinoma cells in vitro (HNSCCs) [4].

High impact information on CASP9

• The majority of Casp9 knockout mice die perinatally with a markedly enlarged and malformed cerebrum caused by reduced apoptosis during brain development [5].
• Cytochrome c-induced proteolytic processing of pro-Casp9 was defective in cytosolic extracts from cells expressing either active Ras or Akt [6].
• The kinase Akt and p21-Ras, an Akt activator, induced phosphorylation of pro-caspase-9 (pro-Casp9) in cells [6].
• Finally, several genes in this pathway, including APAF1, CASP9 and CASP3, have been shown to be associated with dramatic defects in neuronal cell number and brain size when mutated in mice [7].
• Caspase-9 (CASP-9) is an initiator CASP in the apoptosome-driven apoptosis pathway and plays an important role in the development and progression of cancer [3].

Biological context of CASP9

• Overexpression of ICE-LAP6 induces apoptosis in MCF7 breast carcinoma cells [8].
• Interestingly, ICE-LAP6 contains an active site QACGG pentapeptide, rather than the QACRG pentapeptide shared by other family members [8].
• Although CASP9 is included in the region encompassing 1p36 LOH in all neuroblastoma cell lines examined, the remaining CASP9 allele(s) express a functional caspase-9 enzyme [2].
• The status of CASP9 and Apaf-1 expression in numerous neuroblastoma cell lines with/without amplified MYCN and chromosome 1p36 loss-of-heterozygosity (LOH) was therefore examined to test the hypothesis that one or both of these genes are tumor suppressors in neuroblastoma [2].
• Two novel single-nucleotide polymorphisms of the Caspase-9 (CASP9) gene in the Japanese population [9].

Anatomical context of CASP9

• ICE-LAP6, a novel member of the ICE/Ced-3 gene family, is activated by the cytotoxic T cell protease granzyme B [8].

Associations of CASP9 with chemical compounds

• More importantly, ICE-LAP6 is proteolytically processed into an active cysteine protease by granzyme B, an important component of cytotoxic T cell-mediated apoptosis [8].
• Our results strongly suggest that Casp-9-dependent apoptosis plays an important role in cisplatin-induced HNSCC apoptosis [10].

Physical interactions of CASP9

• Molecular modeling supports the conclusion that Arg(10) in the D domain of caspase-9 interacts with Asp(160) in the TTCD motif of ERK2 [11].

Enzymatic interactions of CASP9

• We demonstrate that the pro-enzymes of Mch6 and the lamin-cleaving enzyme Mch2alpha are substrates for mature CPP32 [12].

Regulatory relationships of CASP9

• These data suggest that Mch2alpha and Mch6 are downstream proteases activated in CPP32- and granzyme B-mediated apoptosis [12].
• Mutational analysis revealed that only a small portion of the CED-4 homologous region (residues 456-559) could be deleted without destroying the ability of Apaf-1-(1-559) to activate pro-casp9 [13].

Other interactions of CASP9

• Once activated, ICE-LAP6 is able to cleave the death substrate poly(ADP-ribose) polymerase into signature apoptotic fragments [8].
• In all three lines tested, the use of a specific inhibitor of Casp-9 almost completely blocked cisplatin-induced apoptosis, while the use of Casp-3 and -8 inhibitors resulted in a partial blockade of cisplatin-induced apoptosis [10].

References