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J. Biol. Chem., Vol. 279, Issue 49, 51182-51192, December 3, 2004

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Antiapoptotic Activity of Akt Is Down-regulated by Ca²⁺ in Myocardiac H9c2 Cells

EVIDENCE OF Ca²⁺-DEPENDENT REGULATION OF PROTEIN PHOSPHATASE 2Ac^*

Chie Yasuoka¶, Yoshito Ihara¶||, Satoshi Ikeda, Yoshiyuki Miyahara, Takahito Kondo, and Shigeru Kohno

From the Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute and the Second Department of Internal Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan

Cell survival signaling of the Akt/protein kinase B pathway was influenced by a change in the cytoplasmic free calcium concentration ([Ca²⁺]_i) for over 2 h via the regulation of a Ser/Thr phosphatase, protein phosphatase 2Ac (PP2Ac), in rat myocardiac H9c2 cells. Akt was down-regulated when [Ca²⁺]_i was elevated by thapsigargin, an inhibitor of the endoplasmic reticulum Ca²⁺-ATPase, but was up-regulated when it was suppressed by 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl)ester (BAPTA-AM), a cell permeable Ca²⁺ chelator. The inactivation of Akt was well correlated with the susceptibility to oxidant-induced apoptosis in H9c2 cells. To investigate the mechanism of the Ca²⁺-dependent regulation of Akt via the regulation of PP2A, we examined the transcriptional regulation of PP2Ac in H9c2 cells with Ca²⁺ modulators. Transcription of the PP2Ac gene was increased by thapsigargin but decreased by BAPTA-AM. The promoter activity was examined and the cAMP response element (CRE) was found responsible for the Ca²⁺-dependent regulation of PP2Ac. Furthermore, phosphorylation of CRE-binding protein increased with thapsigargin but decreased with BAPTA-AM. A long term change of [Ca²⁺]_i regulates PP2Ac gene transcription via CRE, resulting in a change in the activation status of Akt leading to an altered susceptibility to apoptosis.

Received for publication, June 28, 2004 , and in revised form, September 3, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY749432.

^* This work was supported in part by grants-in-aid from the Japanese Ministry of Education, Culture, Sports, Science, and Technology through the 21st Century COE program, and by a grant provided by the Ichiro Kanehara 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.

^¶ Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. Tel.: 81-95-849-7099; Fax: 81-95-849-7100; E-mail: y-ihara{at}net.nagasaki-u.ac.jp.

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