Reversal of human cellular senescence: roles of the p53 and p16 pathways

Beausejour, C. M., Krtolica, A., Galimi, F., Narita, M., Lowe, S. W., Yaswen, P., Campisi, J. (August 2003) Reversal of human cellular senescence: roles of the p53 and p16 pathways. Embo Journal, 22 (16). pp. 4212-4222. ISSN 0261-4189

URL: http://www.ncbi.nlm.nih.gov/pubmed/12912919
DOI: 10.1093/emboj/cdg417

Abstract

Telomere erosion and subsequent dysfunction limits the proliferation of normal human cells by a process termed replicative senescence. Replicative senescence is thought to suppress tumorigenesis by establishing an essentially irreversible growth arrest that requires activities of the p53 and pRB tumor suppressor proteins. We show that, depending on expression of the pRB regulator p16, replicative senescence is not necessarily irreversible. We used lentiviruses to express specific viral and cellular proteins in senescent human fibroblasts and mammary epithelial cells. Expression of telomerase did not reverse the senescence arrest. However, cells with low levels of p16 at senescence resumed robust growth upon p53 inactivation, and limited growth upon expression of oncogenic RAS. In contrast, cells with high levels of p16 at senescence failed to proliferate upon p53 inactivation or RAS expression, although they re-entered the cell cycle without growth after pRB inactivation. Our results indicate that the senescence response to telomere dysfunction is reversible and is maintained primarily by p53. However, p16 provides a dominant second barrier to the unlimited growth of human cells.

Item Type: Paper
Additional Information: Embo J.
Uncontrolled Keywords: cyclin-dependent kinase pRB RAS senescence telomerase MAMMARY EPITHELIAL-CELLS HUMAN-DIPLOID FIBROBLASTS REPLICATIVE LIFE-SPAN LARGE TUMOR-ANTIGEN SIMIAN VIRUS-40 DNA-SYNTHESIS TELOMERASE ACTIVITY RETINOBLASTOMA PROTEIN T-ANTIGENS IN-VITRO
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions
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 > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: Matt Covey
Date: August 2003
Date Deposited: 10 Jun 2013 14:24
Last Modified: 10 Jun 2013 14:24
PMCID: PMC175806
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27973

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