DUSP6 is a novel transcriptional target of p53 and regulates p53-mediated apoptosis by modulating expression levels of Bcl-2 family proteins

Abstract

p53 regulates various cellular responses through transcriptional regulation of distinct sets of target genes. Dual specificity phosphatase 6 (DUSP6) is a cytosolic phosphatase that inactivates the extracellular-signal-regulated kinase 1/2 (ERK1/2). This study demonstrates that p53 transactivates DUSP6 in human colorectal HCT116 cells to regulate ERK1/2 in p53-mediated cell death. DUSP6 is transactivated by p53 overexpression and genotoxic agents, and chromatin immunoprecipitation revealed two p53-binding sites in the DUSP6 promoter responsible for DUSP6 induction. Expression of shDUSP6 inhibited 5'-FU-induced cell death, whereas overexpression of DUSP6 increased susceptibility to 5'-FU. 5'-FU treatment dephosphorylated ERK in a DUSP6-dependent manner, resulting in destabilization of Bcl-2 and stabilization of Bad. These results provide insights on the modulatory role of p53 in the survival pathway by up-regulating DUSP6.