title: 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.
authors.affiliation: Department of Biochemistry, Chosun University School of Medicine, 309 Pilmoondaero, Dong-Gu, Gwang-Ju 501-759, Republic of Korea.
authors.forename: Sujan
authors.initials: S
authors.lastname: Piya
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Jeehyeon
authors.initials: J
authors.lastname: Bae
authors.forename: Dai-Wu
authors.initials: DW
authors.lastname: Seol
authors.forename: Ae Ran
authors.initials: AR
authors.lastname: Moon
authors.forename: Tae-Hyoung
authors.initials: TH
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D054642:Dual Specificity Phosphatase 6; D005472:Fluorouracil