title: 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.
  
  
  RESULTS
  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.
authors.affiliation: Experimental Therapeutics Programme, Centro Nacional De Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Ruiz
authors.forename: Magali
authors.initials: M
authors.lastname: Traskine
authors.forename: Irene
authors.initials: I
authors.lastname: Ferrer
authors.forename: Estrella
authors.initials: E
authors.lastname: Castro
authors.forename: Juan F M
authors.initials: JF
authors.lastname: Leal
authors.forename: Marcelline
authors.initials: M
authors.lastname: Kaufman
authors.forename: Amancio
authors.initials: A
authors.lastname: Carnero
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D049109:Cell Proliferation; D016922:Cellular Senescence; D016158:Genes, p53; D006579:Heterozygote; D016018:Least-Squares Analysis; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D010641:Phenotype; D054645:Protein Phosphatase 1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; C517187:PPP1CA protein, human; D054645:Protein Phosphatase 1; D018631:ras Proteins
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