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Molecular and Cellular Biology, June 2009, p. 3379-3389, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.01758-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Extracellular Signal-Regulated Kinase 2-Dependent Phosphorylation Induces Cytoplasmic Localization and Degradation of p21Cip1{triangledown} ,{dagger}

Chae Young Hwang,1 Cheolju Lee,2 and Ki-Sun Kwon1*

Laboratory of Cell Signaling, Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333,1 Life Sciences Division, Korea Institute of Science and Technology, Seoul 136-791, South Korea2

Received 17 November 2008/ Returned for modification 29 December 2008/ Accepted 7 April 2009

p21Cip1 is an inhibitor of cell cycle progression that promotes G1-phase arrest by direct binding to cyclin-dependent 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.

* Corresponding author. Mailing address: Laboratory of Cell Signaling, Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, 52 Oun-Dong, Yusong, Daejeon 305-333, South Korea. Phone: 82-42-860-4143. Fax: 82-42-860-4598. E-mail: kwonks{at}kribb.re.kr

{triangledown} Published ahead of print on 13 April 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, June 2009, p. 3379-3389, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.01758-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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