EGF-mediated induction of Mcl-1 at the switch to lactation is essential for alveolar cell survival.
Expansion and remodelling of the mammary epithelium requires a tight balance between cellular proliferation, differentiation and death. To explore cell survival versus cell death decisions in this organ, we deleted the pro-survival gene Mcl-1 in the mammary epithelium. Mcl-1 was found to be essential at multiple developmental stages including morphogenesis in puberty and alveologenesis in pregnancy. Moreover, Mcl-1-deficient basal cells were virtually devoid of repopulating activity, suggesting that this gene is required for stem cell function. Profound upregulation of the Mcl-1 protein was evident in alveolar cells at the switch to lactation, and Mcl-1 deficiency impaired lactation. Interestingly, EGF was identified as one of the most highly upregulated genes on lactogenesis and inhibition of EGF or mTOR signalling markedly impaired lactation, with concomitant decreases in Mcl-1 and phosphorylated ribosomal protein S6. These data demonstrate that Mcl-1 is essential for mammopoiesis and identify EGF as a critical trigger of Mcl-1 translation to ensure survival of milk-producing alveolar cells.
1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Nai Yang
NY
Fu
1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Anne C
AC
Rios
1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Bhupinder
B
Pal
Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 0200, Australia.
Rina
R
Soetanto
1] Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia [2] Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
Aaron T L
AT
Lun
1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Kevin
K
Liu
1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Tamara
T
Beck
1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Sarah A
SA
Best
1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
François
F
Vaillant
1] Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia [2] Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
Philippe
P
Bouillet
1] Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia [2] Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
Andreas
A
Strasser
1] Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 0200, Australia [2] Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia.
Thomas
T
Preiss
1] Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia [2] Department of Mathematics and Statistics, The University of Melbourne, Parkville, Victoria 3010, Australia.
Gordon K
GK
Smyth
1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia [2] Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia [3] Department of Medicine, The University of Melbourne, Parkville, Victoria 3010, Australia.
Geoffrey J
GJ
Lindeman
1] ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
Jane E
JE
Visvader
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D005260:Female; D055786:Gene Knockout Techniques; D007774:Lactation / Q000235:genetics* / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis / Q000235:genetics*; D010766:Phosphorylation; D011247:Pregnancy; D038601:Ribosomal Protein S6 / Q000378:metabolism; D017423:Sequence Analysis, RNA; D013234:Stem Cells / Q000166:cytology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D015854:Up-Regulation
C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D038601:Ribosomal Protein S6; D004815:Epidermal Growth Factor; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases