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Carcinogenesis Advance Access published online on January 19, 2008
Carcinogenesis, doi:10.1093/carcin/bgm246
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

PPP1CA contributes to the senescence program induced by oncogenic Ras.

Maria E. Castro1, Irene Ferrer1, Alberto Cascón2, Maria V. Guijarro1,4, Matilde Lleonart3, Santiago Ramon y Cajal3, Juan F.M. Leal1, Mercedes Robledo2 and Amancio Carnero1,5

1 Experimental Therapeutics Programme
2 Human Genetics Programme Spanish National Cancer Center (CNIO),Spain
3 Departamento de Patología, Hospital Vall d'Hebron, Barcelona, Spain
4 Present address: Experimental Pathology Program, Department of Pathology, New York University School of Medicine

5 Corresponding author: Experimental Therapeutics Programme, Spanish National Cancer Research Centre, c/ Melchor Fernandez Almagro nº3, 28029 Madrid,Spain. acarnero{at}cnio.es

Ectopic expression of conditional murine p53 (p53val135) and oncogenic ras is enough to induce a senescent-like growth arrest at the restrictive temperature. We took advantage of this cellular system to identify new key players in the ras/p53-induced senescence. Applying a retroviral-based genetic screen we obtained an antisense RNA fragment against PPP1CA, the catalytic subunit of PP1{alpha}, which loss of function bypasses ras/p53-induced growth arrest and senescence. Expression of a specific shRNA against PPP1CA impairs the p53-dependent induction of p21 after DNA damage and blocks the subsequent pRb dephosphorylation, thus bypassing p53-induced arrest. We found that oncogenic ras promotes an increase in the intracellular level of ceramides together with an increase in the PPP1CA protein levels. Addition of soluble ceramide to the cells induced a senescence phenotype which is blocked through PPP1CA downregulation by specific shRNA. Analysis of human tumors suggests that one of the PPP1CA alleles might be lost in a high percentage of carcinomas such as kidney and colorectal. The overexpression of 2 out of 5 PPP1CA alternative spliced variants reduced tumor cell growth and the downregulation of the protein to hemizygosity increased the anchorage independent growth. We propose that oncogenic stress induced by ras cause ceramide accumulation, therefore increasing PPP1CA activity, pRb dephosphorylation and onset of the p53-induced arrest, contributing to tumor suppression.

Key Words: p53 • senescence • genetic screening • PPP1CA • ras • ceramide

Received August 29, 2007; revised October 25, 2007; accepted October 27, 2007.


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