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  • DAPK is a kD Ca calmodulin


    DAPK is a 160-kD Ca2+/calmodulin (CaM)-regulated Ser/Thr kinase that mediates cell death. The activated forms of DAPK and DRP-1 are capable of inducing two distinct cytoplasmic events characteristic of programmed cell death, including membrane blebbing and the formation of autophagic vesicles (Inbal et al., 2002). Although both DAPK and DRP-1 are mediators of autophagy, the different intracellular localization of the two kinases suggests that they are not completely redundant in their mode of action (Inbal et al., 2002). A survey of cancer cell lines derived from various human tumors has shown that the mRNA and protein expression of DAPK were frequently lost (Kissil et al., 1997). DAPK mRNA and protein expression levels were below detection limits in 80% of B cell lymphoma and leukemia cell lines and in 30–40% of cell lines derived from Liquidambaric acid carcinomas, breast carcinomas, and renal cell carcinomas (Katzenellenbogen et al., 1999, Kissil et al., 1997). This initial screening provided the first hint that DAPK expression may be lost in the course of malignant transformation. It also suggested that loss of DAPK expression provides a positive selective advantage during the formation of lung metastases (Inbal et al., 1997). Abnormal patterns of DNA methylation in cancer cells have been recognized for more than 20 years (Brown and Strathdee, 2002). A growing number of cancer genes are being recognized that harbor dense methylation in normally unmethylated promoter CpG islands Liquidambaric acid (Baylin et al., 1998, Jones and Laird, 1999). That this hypermethylation might functionally contribute to loss of gene function generated considerable skepticism that persisted, even after this event was correlated with absent expression of classic tumor suppressor genes (Herman et al., 1994). Hypermethylation of promoter regions, which is associated with transcriptional silencing, is at least as common as DNA mutation as a mechanism for inactivation of classical tumor suppressor genes in human cancers (Jones and Baylin, 2002, Tsou et al., 2002). The aberrant methylation of genes that suppress tumorigenesis appears to occur early in tumor development and increase progressively, eventually leading to the malignant phenotype (Fearon and Vogelstein, 1990, Kim and Mason, 1995). Genes involved in every step of tumorigenesis can be silenced by this epigenetic mechanism. Numerous somatic alterations have been described in bladder cancer, most notably mutation or functional inactivation of the tumor suppressor TP53 (Kelsey et al., 2004, Sidransky et al., 1991). In addition, in vitro evidence also suggests that bladder carcinogens play a crucial role in the induction of important epigenetic alterations. Epigenetic silencing of tumor suppressor genes by promoter hypermethylation has been shown for a variety of genes in bladder cancer. Recently, studies by using real-time PCR to detect specific promoter methylation in bladder cancer have revealed that several genes (e.g. DAPK, RARβ, E-cadherin and RASSF1A) were subsequently found to differ between tumor tissue and normal urothelial tissue and to correlate well with histopathological staging or grading (Catto et al., 2005, Chan et al., 2002). In addition, the promoter methylation of specific genes offers additional prognostic information and is associated with the outcome in patients with nonmuscle invasive and muscle invasive bladder cancer (Christoph et al., 2006). In urothelial carcinomas, a correlation between the methylation of the DAPK-1 promoter and subsequent lack of DAPK-1 protein expression in superficial tumors has been shown (Tada et al., 2002). Furthermore, hypermethylation of DAPK has been found to be a useful prognostic marker for disease recurrence in superficial bladder cancers (Tada et al., 2002). Catto et al. has demonstrated that the DAPK promoter methylation was present in 86% of urothelial carcinoma. In this study, we used MSP and Western blotting to detect the promoter hypermethylation of DAPK gene and DAPK proteins expression in arsenite-treated SV-HUC-1 cells. We found the DAPK gene was hypermethylated and the expression of DAPK protein was decreased by arsenite. This may be one of the mechanisms whereby arsenite salt promotes urothelial carcinogenesis.