Mcl-1 promotes survival of thymocytes by inhibition of Bak in a pathway separate from Bcl-2.
The antiapoptotic proteins Mcl-1 and Bcl-2 have been shown to be critical in T-cell development and homeostasis, but the precise mechanism by which these proteins function in T cells and other cells of the body is unclear. Potential mechanisms have allowed both for overlapping and unique roles for these proteins because of their abilities to bind different proapoptotic Bcl-2 family members, but it is unclear which of these mechanisms are important in an in vivo context. By generation of various genetic mouse models, we found that Mcl-1-deficient thymocytes die largely by a Bak-specific mechanism. In vivo deletion of Bak rescued the survival and developmental blocks of Mcl-1-deficient thymocytes at the double-negative and single-positive stages. Transgenic overexpression of Bcl-2 and in vivo deletion of Bax or Bim were unable to rescue Mcl-1-deficient thymocytes. Thus, Mcl-1 functions in a unique pathway from Bcl-2 in T lymphocytes, likely because of its specific ability to bind and sequester proapoptotic Bak. Together, these data provide an in vivo model for Mcl-1 activity and present us with a greater understanding of the pathways that promote thymocyte survival.
Dunkle
A
A
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Dzhagalov
I
I
He
Y-W
YW
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival; D017353:Gene Deletion; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C579094:Mcl1 protein, mouse; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein