Journal
CELL
Volume 128, Issue 2, Pages 295-308Publisher
CELL PRESS
DOI: 10.1016/j.cell.2006.11.050
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Funding
- NCI NIH HHS [CA106768, CA91922] Funding Source: Medline
- NIAID NIH HHS [AI054696, AI041637] Funding Source: Medline
- NIGMS NIH HHS [GM67101] Funding Source: Medline
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Like apoptosis, oncogene-induced senescence is a barrier to tumor development. However, relatively little is known about the signaling pathways mediating the senescence response. p38regulated/activated protein kinase (PRAK) is a p38 MAIPIK 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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