Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling

Lin, A. W., Barradas, M., Stone, J. C., Van Aelst, L., Serrano, M., Lowe, S. W. (October 1998) Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes & Development, 12 (19). pp. 3008-3019. ISSN 0890-9369

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Abstract

Oncogenic Pas transforms immortal rodent cells to a tumorigenic state, in part, by constitutively transmitting mitogenic signals through the mitogen-activated protein kinase (MAPK) cascade. In primary cells, Pas is initially mitogenic but eventually induces premature senescence involving the p53 and p16(INK4a) tumor suppressors. Constitutive activation of MEK (a component of the MAPK cascade) induces both p53 and p16, and is required for Ras-induced senescence of normal human fibroblasts. Furthermore, activated MEK permanently arrests primary murine fibroblasts but forces uncontrolled mitogenesis and transformation in cells lacking either p53 or INK4a. The precisely opposite response of normal and immortalized cells to constitutive activation of the MAPK cascade implies that premature senescence acts as a fail-safe mechanism to limit the transforming potential of excessive Pas mitogenic signaling. Consequently, constitutive MAPK signaling activates p53 and p16 as tumor suppressors.

Item Type: Paper
Uncontrolled Keywords: MAPK signaling premature senescence MEK tumor suppression p53 p16 CELL-CYCLE ARREST MAP KINASE KINASE HUMAN-DIPLOID FIBROBLASTS C-MYC PROTEIN SKIN TUMORS IN-VIVO REPLICATIVE SENESCENCE COMPLEX-FORMATION RAS ONCOGENES INK4A LOCUS
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Mitogen-activated protein kinase
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence
CSHL Authors:
Communities: CSHL labs > Lowe lab
CSHL labs > Van Aelst lab
Depositing User: Matt Covey
Date: October 1998
Date Deposited: 18 Dec 2013 21:50
Last Modified: 18 Dec 2013 21:50
PMCID: PMC317198
Related URLs:
URI: https://repository.cshl.edu/id/eprint/29107

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