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PMID: 15169907 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Mitogen stimulation cooperates with telomere shortening to activate DNA damage responses and senescence signaling.

Molecular and cellular biology ·Vol. 24 ·No. 12 ·2004-06-00 ·Pages 5459-74

Satyanarayana A, Greenberg RA, Schaetzlein S, Buer J, Masutomi K, Hahn WC, Zimmermann S, Martens U, Manns MP, Rudolph KL

Abstract

Replicative senescence is induced by critical telomere shortening and limits the proliferation of primary cells to a finite number of divisions. To characterize the activity status of the replicative senescence program in the context of cell cycle activity, we analyzed the senescence phenotypes and signaling pathways in quiescent and growth-stimulated primary human fibroblasts in vitro and liver cells in vivo. This study shows that replicative senescence signaling operates at a low level in cells with shortened telomeres but becomes fully activated when cells are stimulated to enter the cell cycle. This study also shows that the dysfunctional telomeres and nontelomeric DNA lesions in senescent cells do not elicit a DNA damage signal unless the cells are induced to enter the cell cycle by mitogen stimulation. The amplification of senescence signaling and DNA damage responses by mitogen stimulation in cells with shortened telomeres is mediated in part through the MEK/mitogen-activated protein kinase pathway. These findings have implications for the further understanding of replicative senescence and analysis of its role in vivo.

MeSH Terms
Animals Base Sequence Cell Cycle/drug effects Cell Division Cells, Cultured Cellular Senescence/genetics DNA Damage DNA, Complementary/genetics Humans Male Mice Mice, Inbred C57BL Mice, Knockout Mitogens/pharmacology Phenotype RNA/genetics Signal Transduction Telomerase/deficiency,genetics Telomere/genetics
Chemicals
DNA, Complementary Mitogens telomerase RNA RNA Telomerase
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Satyanarayana A
Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Germany.
Greenberg R A
Schaetzlein S
Buer J
Masutomi K
Hahn W C
Zimmermann S
Martens U
Manns M P
Rudolph K L
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.12.5459-5474.2004
Published
2004-06-00
Pages
5459-74
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC419883
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.24.12.5459-5474.2004 PMC Full Text View journal details
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