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Molecular and Cellular Biology, April 2007, p. 3187-3198, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.01461-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Glycogen Synthase Kinase 3ß Phosphorylates p21WAF1/CIP1 for Proteasomal Degradation after UV Irradiation{triangledown} ,{dagger}

Ji Young Lee,1,2,3 Su Jin Yu,1,3 Yun Gyu Park,1,3 Joon Kim,2* and Jeongwon Sohn1,3*

Department of Biochemistry, Korea University College of Medicine, Seoul 136-705, South Korea,1 School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, South Korea,2 Korean Institute of Molecular Medicine and Nutrition, Seoul 136-705, South Korea3

Received 8 August 2006/ Returned for modification 4 September 2006/ Accepted 23 January 2007

UV irradiation has been reported to induce p21WAF1/CIP1 protein degradation through a ubiquitin-proteasome pathway, but the underlying biochemical mechanism remains to be elucidated. Here, we show that ser-114 phosphorylation of p21 protein by glycogen synthase kinase 3ß (GSK-3ß) is required for its degradation in response to UV irradiation and that GSK-3ß activation is a downstream event in the ATR signaling pathway triggered by UV. UV transiently increased GSK-3ß activity, and this increase could be blocked by caffeine or by ATR small interfering RNA, indicating ATR-dependent activation of GSK-3ß. ser-114, located within the putative GSK-3ß target sequence, was phosphorylated by GSK-3ß upon UV exposure. The nonphosphorylatable S114A mutant of p21 was protected from UV-induced destabilization. Degradation of p21 protein by UV irradiation was independent of p53 status and prevented by proteasome inhibitors. In contrast to the previous report, the proteasomal degradation of p21 appeared to be ubiquitination independent. These data show that GSK-3ß is activated by UV irradiation through the ATR signaling pathway and phosphorylates p21 at ser-114 for its degradation by the proteasome. To our knowledge, this is the first demonstration of GSK-3ß as the missing link between UV-induced ATR activation and p21 degradation.

* Corresponding author. Mailing address for Jeongwon Sohn: Korea University College of Medicine, 126-1 Anam-Dong 5-Ga, Sungbuk-Gu, Seoul 136-705, South Korea. Phone: 82-2-920-6192. Fax: 82-2-922-6702. E-mail: biojs{at}korea.ac.kr. Mailing address for Joon Kim: School of Life Sciences and Biotechnology, Korea University, 126-1 Anam-Dong 5-Ga, Sungbuk-Gu, Seoul 136-701, South Korea. Phone: 82-2-3290-3442. Fax: 82-2-3290-3442. E-mail: joonkim{at}korea.ac.kr

{triangledown} Published ahead of print on 5 February 2007.

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

Molecular and Cellular Biology, April 2007, p. 3187-3198, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.01461-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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