EGF-mediated induction of Mcl-1 at the switch to lactation is essential for alveolar cell survival

Nat Cell Biol. 2015 Apr;17(4):365-75. doi: 10.1038/ncb3117. Epub 2015 Mar 2.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Base Sequence
  • Cell Differentiation / genetics
  • Cell Line
  • Cell Proliferation / genetics
  • Cell Survival
  • Epidermal Growth Factor / antagonists & inhibitors
  • Epidermal Growth Factor / biosynthesis*
  • Epidermal Growth Factor / metabolism
  • Female
  • Gene Knockout Techniques
  • Lactation / genetics*
  • Lactation / metabolism*
  • Mammary Glands, Animal / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cell Leukemia Sequence 1 Protein / biosynthesis
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics*
  • Phosphorylation
  • Pregnancy
  • Ribosomal Protein S6 / metabolism
  • Sequence Analysis, RNA
  • Stem Cells / cytology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Up-Regulation

Substances

  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Ribosomal Protein S6
  • Epidermal Growth Factor
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse