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J. Biol. Chem., Vol. 283, Issue 7, 3979-3987, February 15, 2008

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Activation of AMP-activated Protein Kinase Induces p53-dependent Apoptotic Cell Death in Response to Energetic Stress^*

Rintaro Okoshi, Toshinori Ozaki, Hideki Yamamoto, Kiyohiro Ando, Nami Koida, Sayaka Ono^¶, Tadayuki Koda^¶, Takehiko Kamijo, Akira Nakagawara¹, and Harutoshi Kizaki²

From the Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717, Oral Health Science Center, Tokyo Dental College, Chiba 261-8502, and ^¶Center for Functional Genomics, Hisamitsu Pharmaceutical Co., Inc., Chiba 260-8717, Japan

Tumor suppressor p53-dependent stress response pathways play an important role in cell fate determination. In this study, we have found that glucose depletion promotes the phosphorylation of AMP-activated protein kinase catalytic subunit (AMPK) in association with a significant up-regulation of p53, thereby inducing p53-dependent apoptosis in vivo and in vitro. Thymocytes prepared from glucose-depleted wild-type mice but not from p53-deficient mice underwent apoptosis, which was accompanied by a remarkable phosphorylation of AMPK and a significant induction of p53 as well as pro-apoptotic Bax. Similar results were also obtained in human osteosarcoma-derived U2OS cells bearing wild-type p53 following glucose starvation. Of note, glucose deprivation led to a significant accumulation of p53 phosphorylated at Ser-46, but not at Ser-15 and Ser-20, and a transcriptional induction of p53 as well as proapoptotic p53 AIP1. Small interference RNA-mediated knockdown of p53 caused an inhibition of apoptosis following glucose depletion. Additionally, apoptosis triggered by glucose deprivation was markedly impaired by small interference RNA-mediated depletion of AMPK. Under our experimental conditions, down-regulation of AMPK caused an attenuation of p53 accumulation and its phosphorylation at Ser-46. In support of these observations, enforced expression of AMPK led to apoptosis and resulted in an induction of p53 at protein and mRNA levels. Furthermore, p53 promoter region responded to AMPK and glucose deprivation as judged by luciferase reporter assay. Taken together, our present findings suggest that AMPK-dependent transcriptional induction and phosphorylation of p53 at Ser-46 play a crucial role in the induction of apoptosis under carbon source depletion.

Received for publication, June 26, 2007 , and in revised form, September 12, 2007.

^* This work was supported in part by a grant-in-aid from the Ministry of Health, Labor and Welfare for Third Term Comprehensive Control Research for Cancer, a grant-in-aid for scientific research on priority areas from the Ministry of Education, Culture, Sports, Science and Technology, Japan, a grant-in-aid for scientific research from Japan Society for the Promotion of Science, and a grant from Uehara Memorial Foundation. 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 Figs. S1 and S2.

¹ To whom correspondence may be addressed. Tel.: 81-43-264-5431; Fax: 81-43-265-4459; E-mail: akiranak{at}chiba-cc.jp. ² To whom correspondence may be addressed. Tel.: 81-43-270-3750; Fax: 81-43-270-3752; E-mail: kizaki{at}tdc.ac.jp.

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