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.