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

Akiko Hashimoto,Kenzo Hirose,Masamitsu Iino

doi:10.1074/jbc.m409363200

Akiko Hashimoto, Kenzo Hirose + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m409363200

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Abstract

BAD, a member of the Bcl-2 protein family, promotes mitochondria-dependent apoptosis. Here, we report that BAD dissociates from 14-3-3zeta 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 14-3-3zeta 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.

Highlights

Growth factors are required for cell growth, proliferation, and differentiation
We showed that BAD dissociates from 14-3-3␨ at the G2/M phase of each cell cycle
The dissociation of BAD from 14-3-3␨ at the G2/M phase does not immediately promote apoptosis but facilitates subsequent apoptosis only when the cells are deprived of growth factors

Summary

Introduction

Growth factors are required for cell growth, proliferation, and differentiation. The deprivation of appropriate growth factors induces apoptosis, causing elimination of hematopoietic cells [1]. Upon deprivation of growth factors, BAD is dephosphorylated and dissociates from 14-3-3 to bind to Bcl-xL or Bcl-2 on the mitochondria, and the translocation of BAD will reduce the threshold for apoptosis and markedly enhance cell death (4 – 6). These reactions are regulated by the phosphorylation states of BAD. If Cdc phosphorylates Ser-128 of BAD in proliferating cells, it is possible that the association between BAD and 14-3-3 is regulated by growth factors and by the cell cycle. These results demonstrate a novel cell cycle-dependent regulation of apoptosis by BAD

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