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Bax activation by the BH3-only protein Puma promotes cell dependence on antiapoptotic Bcl-2 family members

¹ Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 892, Département de Recherche en Cancérologie, F-44035 Nantes, Cedex 01, France
² Faculté de Médecine, Université de Nantes, F-44035 Nantes, Cedex 01, France
³ Institut de Recherche Servier, Département Cancer, 78290 Croissy sur Seine, France
⁴ Centre National de la Recherche Scientifique Unité Mixte de Recherche 5095, Université de Bordeaux 2, F-33077 Bordeaux, France

Correspondence to Philippe Juin: Philippe.Juin{at}univ-nantes.fr

It is still unclear whether the BH3-only protein Puma (p53 up-regulated modulator of apoptosis) can prime cells to death and render antiapoptotic BH3-binding Bcl-2 homologues necessary for survival through its ability to directly interact with proapoptotic Bax and activate it. In this study, we provide further evidence, using cell-free assays, that the BH3 domain of Puma binds Bax at an activation site that comprises the first helix of Bax. We also show that, in yeast, Puma interacts with Bax and triggers its killing activity when Bcl-2 homologues are absent but not when Bcl-xL is expressed. Finally, endogenous Puma is involved in the apoptotic response of human colorectal cancer cells to the Bcl-2/Bcl-xL inhibitor ABT-737, even in conditions where the expression of Mcl-1 is down-regulated. Thus, Puma is competent to trigger Bax activity by itself, thereby promoting cellular dependence on prosurvival Bcl-2 family members.

Abbreviations used in this paper: BdGBM, Bax-deficient GBM; BeGBM, Bax-expressing GBM; GBM, glioblastoma multiforme; H1-Cter, H1 C terminus; Puma, p53 up-regulated modulator of apoptosis; scr, scramble.

© 2009 Gallenne et al.
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