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J. Biol. Chem., Vol. 283, Issue 25, 17702-17711, June 20, 2008

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PDK1 Regulates Cell Proliferation and Cell Cycle Progression through Control of Cyclin D1 and p27^Kip1 Expression^*

Kyoko Nakamura, Hiroshi Sakaue¹, Akihiko Nishizawa, Yasushi Matsuki, Hideyuki Gomi, Eijiro Watanabe, Ryuji Hiramatsua, Mimi Tamamori-Adachi^¶, Shigetaka Kitajima^¶, Tetsuo Noda^||, Wataru Ogawa, and Masato Kasuga

From the Department of Internal Medicine, Division of Diabetes, Metabolism, and Endocrinology, Kobe University Graduate School of Medicine, Kobe 650-0017, Genomics Science Laboratories, Sumitomo Pharmaceuticals Company, Ltd., Takarazuka 665-0051, the ^¶Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, and the ^||Department of Cell Biology, Japanese Foundation for Cancer Research, Cancer Institute, Tokyo 170-8455, Japan

PDK1 (3-phosphoinositide-dependent protein kinase 1) is a key mediator of signaling by phosphoinositide 3-kinase. To gain insight into the physiological importance of PDK1 in cell proliferation and cell cycle control, we established immortalized mouse embryonic fibroblasts (MEFs) from mice homozygous for a "floxed" allele of Pdk1 and from wild-type mice. Introduction of Cre recombinase by retrovirus-mediated gene transfer resulted in the depletion of PDK1 in Pdk1^lox/lox MEFs but not in Pdk1^+/+ MEFs. The insulin-like growth factor-1-induced phosphorylation of various downstream effectors of PDK1, including Akt, glycogen synthase kinase 3, ribosomal protein S6, and p70 S6 kinase, was markedly inhibited in the PDK1-depleted (Pdk1-KO) MEFs. The rate of serum-induced cell proliferation was reduced; progression of the cell cycle from the G₀-G₁ phase to the S phase was delayed, and cell cycle progression at G₂-M phase was impaired in Pdk1-KO MEFs. These cells also manifested an increased level of p27^Kip1 expression and a reduced level of cyclin D1 expression during cell cycle progression. The defect in cell cycle progression from the G₀-G₁ to the S phase in Pdk1-KO MEFs was rescued by forced expression of cyclin D1, whereas rescue of the defect in G₂-M progression in these cells required both overexpression of cyclin D1 and depletion of p27^Kip1 by RNA interference. These data indicate that PDK1 plays an important role in cell proliferation and cell cycle progression by controlling the expression of both cyclin D1 and p27^Kip1.

Received for publication, April 3, 2008 , and in revised form, April 21, 2008.

^* This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) (to H. S. and M. K.), a grant for the 21st Century COE Program "Center of Excellence for Signal Transduction Disease: Diabetes Mellitus as Model" from MEXT (to M. K.), a grant for the Cooperative Link of Unique Science and Technology for Economy Revitalization from MEXT (to M. K.), a grant-in-aid for creative scientific research from the Japan Society for the Promotion of Science (to M. K.), a grant-in-aid for scientific research on priority areas from MEXT (to H. S.), and a grant-in-aid for scientific research (C) from Japan Society for the Promotion of Science (to H. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1 and S2.

¹ To whom correspondence should be addressed: Division of Pharmacology, Kinki University School of Medicine, 377-2 Onohigashi, Osakasayama, Osaka 589-8511, Japan. Tel.: 81-72-366-0221; Fax: 81-72-366-1820; E-mail: hsakaue{at}med.kindai.ac.jp.

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