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Modulation of replicative senescence of diploid human cells by nuclear ERK signaling
Journal article   Open access   Peer reviewed

Modulation of replicative senescence of diploid human cells by nuclear ERK signaling

Maria Tresini, Antonello Lorenzini, Claudio Torres and Vincent J Cristofalo
The Journal of biological chemistry, v 282(6), pp 4136-4151
09 Feb 2007
DOI: https://doi.org/10.1074/jbc.M604955200
PMID: 17145763
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1074/jbc.M604955200View
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Abstract

Amino Acid Substitution - genetics Cell Line Cell Nucleus - enzymology Cell Nucleus - genetics Cell Proliferation Cellular Senescence - genetics Diploidy Dual-Specificity Phosphatases Extracellular Signal-Regulated MAP Kinases - physiology Fibroblasts - cytology Fibroblasts - enzymology Growth Inhibitors - physiology Humans MAP Kinase Signaling System - genetics Mitogen-Activated Protein Kinase 1 - genetics Mitogen-Activated Protein Kinase 1 - physiology Mitogen-Activated Protein Kinase Phosphatases Protein Tyrosine Phosphatases - biosynthesis Protein Tyrosine Phosphatases - deficiency Protein Tyrosine Phosphatases - genetics Protein Tyrosine Phosphatases - physiology
Normal somatic cells have a limited replicative lifespan, and serial subcultivation ultimately results in senescence. Senescent cells are irreversibly growth-arrested and show impaired responses to mitogens. Activation of the ERK signaling pathway, an absolute requirement for cell proliferation, results in nuclear relocalization of active ERKs, an event impaired in senescent fibroblasts. This impairment coincides with increased activity of the nuclear ERK phosphatase MKP2. Here we show that replicative lifespan can be altered by changes in nuclear ERK activity. Ectopic expression of MKP2 results in premature senescence. In contrast, knock-down of MKP2 expression, through transduction of MKP2 sequence-specific short hairpin RNA, or expression of the phosphatase resistant ERK2(D319N) mutant, abrogates the effects of increased endogenous MKP2 levels and senescence is postponed. Nuclear targeting of ERK2(D319N) significantly augments its effects and the transduced cultures show higher than 60% increase in replicative lifespan compared with cultures transduced with wt ERK2. Long-lived cultures senesce with altered molecular characteristics and retain the ability to express c-fos, and Rb is maintained in its inactive form. Our results support that MKP2-mediated inactivation of nuclear ERK2 represents a key event in the establishment of replicative senescence. Although it is evident that senescence can be imposed through multiple mechanisms, restoration of nuclear ERK activity can bypass a critical senescence checkpoint and, thus, extend replicative lifespan.

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53 citations in Web of Science
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Collaboration types
Domestic collaboration
Web of Science research areas
Biochemistry & Molecular Biology
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