BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak (original) (raw)

  1. Wei-Xing Zong1,
  2. Tullia Lindsten1,
  3. Andrea J. Ross2,
  4. Grant R. MacGregor3, and
  5. Craig B. Thompson1,4
  6. 1Departments of Medicine, Cancer Biology, and Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; 2Graduate Program in Biochemistry, Cell and Developmental Biology, and 3Center for Molecular Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA

Abstract

The BH3-only proteins Bim and Bad bind to the antiapoptotic Bcl-2 proteins and induce apoptosis in wild-type cells and cells from either_bax_ −/− or bak −/− animals. In contrast, constitutively active forms of Bim and Bad failed to induce apoptosis in bax −/− bak −/− cells. Expression of Bax restored susceptibility of the cells to Bim and Bad. In addition, Bax but not Bim or Bad sensitized the_bax_ −/− bak −/− cells to a wide variety of cell death stimuli including UV irradiation, chemotherapeutic agents, and ER stress. These results suggest that neither activation of BH3-only proteins nor suppression of pro-survival Bcl-2 proteins is sufficient to kill cells in the absence of both Bax and Bak. Furthermore, whereas mouse embryo fibroblasts (MEF) expressing only Bax or Bak displayed resistance to transformation,bax −/− bak −/− MEF were nearly as prone to oncogenic transformation as p53 −/− MEF. Thus, the function of either Bax or Bak appears required to initiate most forms of apoptosis and to suppress oncogenic transformation.

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