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Characterization of the p53 response to oncogene-induced senescence.

ABSTRACT: BACKGROUND: P53 activation can trigger various outcomes, among them reversible growth arrest or cellular senescence. It is a live debate whether these outcomes are influenced by quantitative or qualitative mechanisms. Furthermore, the relative contribution of p53 to Ras-induced senescence is also matter of controversy. METHODOLOGY/PRINCIPAL FINDINGS: This study compared situations in which different signals drove senescence with increasing levels of p53 activation. The study revealed that the levels of p53 activation do not determine the outcome of the response. This is further confirmed by the clustering of transcriptional patterns into two broad groups: p53-activated or p53-inactivated, i.e., growth and cellular arrest/senescence. Furthermore, while p53-dependent transcription decreases after 24 hrs in the presence of active p53, senescence continues. Maintaining cells in the arrested state for long periods does not switch reversible arrest to cellular senescence. Together, these data suggest that a Ras-dependent, p53-independent, second signal is necessary to induce senescence. This study tested whether PPP1CA (the catalytic subunit of PP1alpha), recently identified as contributing to Ras-induced senescence, might be this second signal. PPP1CA is induced by Ras; its inactivation inhibits Ras-induced senescence, presumably by inhibiting pRb dephosphorylation. Finally, PPP1CA seems to strongly co-localize with pRb only during senescence. CONCLUSIONS: The levels of p53 activation do not determine the outcome of the response. Rather, p53 activity seems to act as a necessary but not sufficient condition for senescence to arise. Maintaining cells in the arrested state for long periods does not switch reversible arrest to cellular senescence. PPP1CA is induced by Ras; its inactivation inhibits Ras-induced senescence, presumably by inhibiting pRb dephosphorylation. Finally, PPP1CA seems to strongly co-localize with pRb only during senescence, suggesting that PP1alpha activation during senescence may be the second signal contributing to the irreversibility of the senescent phenotype.

SUBMITTER: Ruiz L

PROVIDER: S-EPMC2535567 | biostudies-other | 2008

REPOSITORIES: biostudies-other

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Characterization of the p53 response to oncogene-induced senescence.

Ruiz Lidia L Traskine Magali M Ferrer Irene I Castro Estrella E Leal Juan F M JF Kaufman Marcelline M Carnero Amancio A

PloS one 20080918 9

<h4>Background</h4>P53 activation can trigger various outcomes, among them reversible growth arrest or cellular senescence. It is a live debate whether these outcomes are influenced by quantitative or qualitative mechanisms. Furthermore, the relative contribution of p53 to Ras-induced senescence is also matter of controversy.<h4>Methodology/principal findings</h4>This study compared situations in which different signals drove senescence with increasing levels of p53 activation. The study reveale ...[more]

PMID: 18800172

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Project description:This experiment was designed to study oncogene-induced senescence (OIS). To this end we generated a series of cell lines derived from normal human diploid fibroblasts IMR90 forced to express the catalytic subunit of telomerase (hTERT). This cells were then subjected to further manipulation by orderly introducing defined genetic elements by retroviral transduction. The first cell line generated was ITV, which was obtained from the original cell line (IMR90 with hTERT) after introducing an empty vector. Subsequently, we introduced Mek:ER, which is a switchable version of the Mek kinase, a relevant downstream effector of Ras signaling during Ras-induced senescence, to generate ITM cells. We further modified this cell line by introducing SV40 small-t antigen (ST), papillomavirus oncoproteins E6 and E7 (E6/E7) or the combination of both (E6/E7 and ST). In this manner, we obtained ITMST, ITME6E7 and ITME6E7ST respectively. This cellular system allow us to have a representation of the different steps into neoplastic transformation. ITM and ITMST cells respond to Mek activation by inducing OIS. ITME6E7 and ITME6E7ST cells do not enter OIS after Mek activation. Mek activation is achieved by treating all cell cultures with 4-hydroxytamoxifen (4OHT) at 100 nM, in the absence of serum, and for 3 days. The gene expression profile of ITV cells served as a reference for all the expression values obtained with the rest of the cell lines. Thus, we ended up with the expression profiles of two cell lines representing oncogene-induced senescence (ITM and ITMST), and two cell lines representing bypass of oncogene-induced senescence, plus a reference profile provided by ITV, the cell line from which all the other cell lines were derived. Our final goal was to identify markers of the oncogene-induced senescence response by comparing the expression profiles of the cell lines entering OIS after Mek activation (that is, after 4OHT treatment) with the ones bypassing this response. Keywords: other

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Characterization of the p53 response to oncogene-induced senescence.

Publications

Characterization of the p53 response to oncogene-induced senescence.

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