Roscovitine-activated HIP2 kinase induces phosphorylation of wt p53 at Ser-46 in human MCF-7 breast cancer cells

✍ Scribed by Józefa Węsierska-Gądek; M. Lienhard Schmitz; Carmen Ranftler

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 314 KB
• Volume: 100
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.21211

✦ Synopsis

Abstract

Human MCF‐7 breast cancer cells are relatively resistant to conventional chemotherapy due to the lack of caspase‐3 activity. We reported recently that roscovitine (ROSC), a potent cyclin‐dependent kinase 2 inhibitor, arrests human MCF‐7 breast cancer cells in the G~2~ phase of the cell cycle and concomitantly induces apoptosis. Exposure of MCF‐7 cells to ROSC also strongly activates the wt p53 tumor suppressor protein in a time‐ and dose‐dependent manner. The p53 level increased despite upregulation of Hdm‐2 protein and was attributable to the site‐specific phosphorylation at Ser‐46. The p53 protein phosphorylated at serine 46 causes the up‐regulation of the p53AIP1 protein, a component of mitochondria. In the present study we identified the pathway mediating ROSC‐induced p53 activation. Exposure of MCF‐7 cells to ROSC activated homeodomain‐intereacting protein kinase‐2 (HIPK2). The overexpression of wild‐type but not kinase inactive HIPK2 increased the basal and ROSC‐induced level of p53 phosphorylation at Ser‐46 and strongly enhanced the rate of apoptosis in cells exposed to ROSC. We show that HIPK2 is activated by ROSC and mediates ROSC‐induced P‐Ser‐46‐p53, thereby stabilizing wt p53 and increasing the efficacy of drug‐induced apoptosis in MCF‐7 cells. These results identify HIPK2 as a component of the ROSC‐induced signaling pathway leading to the stabilization and activation of wt p53 protein. J. Cell. Biochem. 100: 865–874, 2007. © 2007 Wiley‐Liss, Inc.