title: Enhanced stability of Mcl1, a prosurvival Bcl2 relative, blunts stress-induced apoptosis, causes male sterility, and promotes tumorigenesis.
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 prosurvival activity. Under unstressed conditions, the modified Mcl1 is present at levels comparable to the native protein, but it is markedly stabilized in cells subjected to stresses, such as protein synthesis inhibition or UV irradiation. Strikingly, the modified Mcl1 allele could genetically complement the loss of Bcl2, because introduction of even a single allele significantly ameliorated the severe polycystic kidney disease and consequent runting caused by Bcl2 loss. Significantly, the development of c-MYC-induced acute myeloid leukemia was also accelerated in mice harboring that Mcl1 allele. Our collective findings reveal that, under certain circumstances, the N terminus of Mcl1 regulates its degradation; that some cell types require degradation of Mcl1 to induce apoptosis; and, most importantly, that rapid turnover of Mcl1 can serve as a tumor-suppressive mechanism.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, VIC 3052, Australia.
authors.forename: Toru
authors.initials: T
authors.lastname: Okamoto
authors.forename: Leigh
authors.initials: L
authors.lastname: Coultas
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.forename: Mark F
authors.initials: MF
authors.lastname: van Delft
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Glaser
authors.forename: Megumi
authors.initials: M
authors.lastname: Takiguchi
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
authors.forename: Philippe
authors.initials: P
authors.lastname: Bouillet
authors.forename: Jerry M
authors.initials: JM
authors.lastname: Adams
authors.forename: David C S
authors.initials: DC
authors.lastname: Huang
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000502:physiology*; D007690:Polycystic Kidney Diseases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D013091:Spermatogenesis; D013737:Testis / Q000473:pathology; D013997:Time Factors; D014466:Ultraviolet Rays
chemical_list: C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc
keywords: programmed cell death; protein turnover