EVI1 targets DELTANp63 and upregulates the cyclin dependent kinase inhibitor p21 independent of p53 to delay cell cycle progression and cell proliferation in colon cancer cells

摘要

Several lines of evidence suggest that specific transcriptional events are involved in cell cycle, proliferation and differentiation processes; however, their deregulation by proto-oncogenes are involved in the development of leukemia and tumors. One such proto-oncogene is ecotropic viral integration site I which can differentially effect cell cycle progression and proliferation, in cell types of different origin. Our data for the first time shows that ecotropic viral integration site I binds to DELTANp63 promoter element directly and down regulates its expression. Down regulation of DELTANp63 induces the expression of p21 in HT-29 cells and also in colon carcinoma cells that do not express p53 including patient samples expressing low level of p53, that eventually delay cell cycle progression at G0/G1 phase. Concomitant silencing of ecotropic viral integration site I from the cells or introduction of DELTANp63 to the cells significantly rescued this phenotype, indicating the growth defect induced by DELTANp63 deficiency to be, at least in part, attributable to ecotropic viral integration site I function. The mutual regulation between ecotropic viral integration site I and DELTANp63 may constitute a novel axis which might affect the downstream pathways in cells that do not express functional p53.