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PRAK is essential for ras-induced senescence and tumor suppression
Authors:Sun Peiqing  Yoshizuka Naoto  New Liguo  Moser Bettina A  Li Yilei  Liao Rong  Xie Changchuan  Chen Jianming  Deng Qingdong  Yamout Maria  Dong Meng-Qiu  Frangou Costas G  Yates John R  Wright Peter E  Han Jiahuai
Institution:Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. pqsun@scripps.edu
Abstract:Like apoptosis, oncogene-induced senescence is a barrier to tumor development. However, relatively little is known about the signaling pathways mediating the senescence response. p38-regulated/activated protein kinase (PRAK) is a p38 MAPK substrate whose physiological functions are poorly understood. Here we describe a role for PRAK in tumor suppression by demonstrating that PRAK mediates senescence upon activation by p38 in response to oncogenic ras. PRAK deficiency in mice enhances DMBA-induced skin carcinogenesis, coinciding with compromised senescence induction. In primary cells, inactivation of PRAK prevents senescence and promotes oncogenic transformation. Furthermore, we show that PRAK activates p53 by direct phosphorylation. We propose that phosphorylation of p53 by PRAK following activation of p38 MAPK by ras plays an important role in ras-induced senescence and tumor suppression.
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