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J. Biol. Chem., Vol. 280, Issue 28, 26225-26232, July 15, 2005

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BAD Detects Coincidence of G₂/M Phase and Growth Factor Deprivation to Regulate Apoptosis^*

Akiko Hashimoto, Kenzo Hirose, and Masamitsu Iino

From the Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan

BAD, a member of the Bcl-2 protein family, promotes mitochondria-dependent apoptosis. Here, we report that BAD dissociates from 14-3-3 at each G₂/M phase of proliferating lymphoid cells. The cell cycle-dependent dissociation of BAD was associated with phosphorylation at Ser-128, whereas mutant S128A-BAD, in which Ser-128 was converted to alanine, remained associated with 14-3-3 throughout the cell cycle. Although the cell cycle-dependent dissociation of BAD per se did not induce apoptosis, growth factor deprivation induced prompt apoptosis at the G₂/M phase but not at the G₁ phase. In cells expressing S128A-BAD, growth factor deprivation-induced apoptosis was markedly delayed and was accompanied by a delayed dephosphorylation of growth factor-dependent regulatory serine residues. These results indicate that BAD induces apoptosis upon detecting the coincidence of G₂/M phase and growth factor deprivation.

Received for publication, August 16, 2004 , and in revised form, April 27, 2005.

^* This work was supported by grants-in-aid for scientific research and by the Advanced and Innovational Research Program in Life Science from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. 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 five supplemental figures.

To whom correspondence should be addressed. Tel.: 81-3-5841-3414; Fax: 81-3-5841-3390; E-mail: iino{at}m.u-tokyo.ac.jp.

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