Cell
Volume 128, Issue 2, 26 January 2007, Pages 295-308
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Article
PRAK Is Essential for ras-Induced Senescence and Tumor Suppression

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Summary

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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6

These authors contributed equally to this work.

7

Present address: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 South Ashland Avenue (M/C 669), Chicago, IL 60607, USA.

8

Present address: Kalypsys, Inc., 10420 Wateridge Circle, San Diego, CA 92121, USA.