Journal article
Enhanced stability of Mcl1, a prosurvival Bcl2 relative, blunts stress-induced apoptosis, causes male sterility, and promotes tumorigenesis
T Okamoto, L Coultas, D Metcalf, MF Van Delft, SP Glaser, M Takiguchi, A Strasser, P Bouillet, JM Adams, DCS Huang
Proceedings of the National Academy of Sciences of the United States of America | Published : 2014
Abstract
The B-cell CLL/lymphoma 2 (Bcl2) relative Myeloid cell leukemia sequence 1 (Mcl1) is essential for cell survival during development and for tissue homeostasis throughout life. Unlike Bcl2, Mcl1 turns over rapidly, but the physiological significance of its turnover has been unclear. We have gained insight into the roles of Mcl1 turnover in vivo by analyzing mice harboring a modified allele of Mcl1 that serendipitously proved to encode an abnormally stabilized form of Mcl1 due to a 13-aa N-terminal extension. Although the mice developed normally and appeared unremarkable, the homozygous males unexpectedly proved infertile due to defective spermatogenesis, which was evoked by enhanced Mcl1 pros..
View full abstractGrants
Awarded by Australian National Health and Medical Research Council
Funding Acknowledgements
We thank P. Colman, S. Cory, P. Czabotar, R. Dickins, P. Kelly, S. L. Khaw, K. Mason, D. Segal, M. Okada, and C. Oneyama for discussions and suggestions; C. Borner, B. Kile, D. Loh, the late S. Korsmeyer, N. Motoyama, and C. Thompson for gifts of reagents and mouse strains; AbbVie for ABT-737; J. Corbin, L. Di Rago, A. Georgiou, H. Ierino, A. Mifsud, A. Srikumar, and E. Trounson for technical assistance; T. Camillieri, H. Donatucci, K. McKenzie, G. Siciliano, E. Sutherland, and K. Trueman for animal husbandry; E. Tsui for histology; and K. Aumann for editing. This work is supported by scholarships, fellowships, and grants from the University of Melbourne (International Research Scholarship to M.F.v.D.), the Australian Research Council (Discovery Early Career Researcher Award to T.O. and Future Fellowship to L.C.), the Australian National Health and Medical Research Council (Career Development Award to P.B.; Research Fellowships to A.S., J.M.A., and D.C.S.H.; Australia Fellowship to A.S.; Project Grants to L.C. and D.C.S.H.; Program Grants 461219, 461221, and 1016701; and Independent Research Institutes Infrastructure Support Scheme Grant 361646), the Cancer Council Victoria (fellowships to M.F.v.D. and D.M.; grants-in-aid to A.S. and D.C.S.H.), the Leukemia and Lymphoma Society (Specialized Centers of Research Grants), the Australian Cancer Research Foundation, and a Victorian State Government Operational Infrastructure Support Grant.