Journal article
Apoptosis is triggered when prosurvival Bcl-2 proteins cannot restrain Bax
JI Fletcher, S Meusburger, CJ Hawkins, DT Riglar, EF Lee, WD Fairlie, DCS Huang, JM Adams
Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2008
Abstract
A central issue in the control of apoptosis is whether its essential mediators Bax and Bak must be restrained by Bcl-2-like prosurvival relatives to prevent their damaging mitochondria and unleashing apoptosis. The issue is particularly vexed for Bax, which is largely a cytosolic monomer in unstressed cells. To determine whether Bax regulation requires its binding by prosurvival relatives, we replaced a conserved aspartate in its BH3 interaction domain with arginine. Bax D68R functioned and behaved like wild-type Bax in localization and activation but had greatly impaired binding to the prosurvival family members. Nevertheless, Bcl-xL remained able to block apoptosis induced by Bax D68R. Whe..
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Awarded by The Cancer Council Victoria
Awarded by Australian National Health and Medical Research Council
Awarded by U.S. National Cancer Institute
Awarded by Leukemia and Lymphoma Society
Funding Acknowledgements
We thank J. Blyth, D. Cooper, H. lerino, T. Pham, K. Pioch, G. Siciliano, and the Walter and Eliza Hall Institute of Medical Research Flow Cytometry Laboratory for excellent technical assistance and animal husbandry; and Abbott Laboratories, R. Anderson, P. Bouillet, L. Chen, P. Colman, S. Cory, P. Czabotar, C. Day, G. Dewson, P. Ferrer, M. Hardwick, M. Hemann, R. Kluck, P. Kelly, the late S. Korsmeyer, M. Kvansakul, D. Loh, N. Motoyama, L. O'Reilly, A. Strasser, C. Thompson, M. van Delft, W. Welch, S. Willis, and M. Yabal for gifts of essential reagents, discussions, and technical advice. This work is supported by grants and fellowships from The Cancer Council Victoria (Project Grant 461239, studentship to D.T.R., scholarship to E.F.L.), the Australian National Health and Medical Research Council (Project Grant 433007, Program Grant 461221, and fellowships to J.I.F., C.J.H., W.D.F., J.M.A., and D.C.S.H.), the U.S. National Cancer Institute (CA80188), and the Leukemia and Lymphoma Society (SCOR 7015-02).