Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21Cip1

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Title
Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21Cip1
Author(s)
Chae Young Hwang; C Lee; Ki Sun Kwon
Bibliographic Citation
Molecular and Cellular Biology, vol. 29, no. 12, pp. 3379-3389
Publication Year
2009
Abstract
p21Cip1 is an inhibitor of cell cycle progression that promotes G1-phase arrest by direct binding to cyclindependent kinase and proliferating cell nuclear antigen. Here we demonstrate that mitogenic stimuli, such as epidermal growth factor treatment and oncogenic Ras transformation, induce p21Cip1 downregulation at the posttranslational level. This downregulation requires the sustained activation of extracellular signal-regulated kinase 2 (ERK2), which directly interacts with and phosphorylates p21Cip1, promoting p21Cip1 nucleocytoplasmic translocation and ubiquitin-dependent degradation, thereby resulting in cell cycle progression. ERK1 is not likely involved in this process. Phosphopeptide analysis of in vitro ERK2-phosphorylated p21Cip1 revealed two phosphorylation sites, Thr57 and Ser130. Double mutation of these sites abolished ERK2-mediated p21Cip1 translocation and degradation, thereby impairing ERK2-dependent cell cycle progression at the G1/S transition. These results indicate that ERK2 activation transduces mitogenic signals, at least in part, by downregulating the cell cycle inhibitory protein p21Cip1.
ISSN
0270-7306
Publisher
Amer Soc Microb
DOI
http://dx.doi.org/10.1128/MCB.01758-08
Type
Article
Appears in Collections:
Aging Convergence Research Center > 1. Journal Articles
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