Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway
Abstract
In spite of the large number of biochemical studies contributing to the analysis of Ras-mediated cell cycle regulation, we do not know how Ras signaling controls the cell cycle. Here, we used an unbiased genetic approach to unveil essential components of Ras-mediated proliferation. Our results reveal that Ras signaling induces cell proliferation by a mechanism that requires inactivation of the p53/p21 Cdk-interacting protein 1 (Cip1) axis by preventing acetylation of specific p53 lysine residues. More importantly, loss of p53 or p21Cip1 can sustain cell proliferation in the absence of Ras proteins via Ras-independent activation of the Raf/Mek/Erk cascade. These results may have important implications for tumor growth and treatment, because activation of Ras oncogenes and inactivation of p53 are frequent events in human cancer.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- October 2014
- DOI:
- 10.1073/pnas.1417549111
- Bibcode:
- 2014PNAS..11115155D