Inhibition of mammary epithelial apoptosis and sustained phosphorylation of Akt/PKB in MMTV-IGF-II transgenic mice.
IGF-II is a growth factor implicated in human cancers and animal tumor models. While the mitogenic properties of IGF-II are well documented, its ability to suppress apoptosis in vivo has never been proven. We generated independent MMTV-IGF-II transgenic mice to examine the control of epithelial apoptosis at the morphological, cellular and molecular levels during the physiological event of postlactation mammary involution. Transgenic IGF-II expression was achieved in mammary epithelium and increased IGF-II bioactivity was confirmed by phosphorylation of the insulin receptor substrate-1, a signaling molecule downstream of the type I IGF receptor. IGF-II overexpression induced a delay in mammary involution, as evident by increased mammary gland to body weight ratios and persistence of both functionally intact lobulo-alveoli and mammary epithelial cellularity. The delayed mammary involution resulted from a significant reduction in mammary epithelial apoptosis, and not from increased epithelial proliferation. Recombinant IGF-II pellets implanted into involuting mammary glands of wild-type mice provided further evidence that IGF-II protein inhibited local epithelial apoptosis. At the molecular level, phosphorylated Akt/PKB, but not Erk1 or Erk2, persisted in IGF-II overexpressors and temporally correlated with reduced epithelial apoptosis. Levels of the phosphatase PTEN were unaltered in the transgenic tissue suggesting that the maintenance of Akt/PKB phosphorylation resulted from sustained phosphorylation rather than altered dephosphorylation of PIP-3. Together, this data reveal that IGF-II inhibits apoptosis in vivo and this effect correlates with prolonged phosphorylation of Akt/PKB
Moorehead
R A
RA
Department of Medical Biophysics, Ontario Cancer Institute/University Health Network, University of Toronto, Toronto, Ontario, M5G 2M9, Canada.
Fata
J E
JE
Johnson
M B
MB
Khokha
R
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004343:Drug Implants; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007335:Insulin-Like Growth Factor II / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D007774:Lactation / Q000502:physiology; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051059:PTEN Phosphohydrolase; D010750:Phosphoproteins / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019076:Transgenes; D025521:Tumor Suppressor Proteins
D004343:Drug Implants; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D007335:Insulin-Like Growth Factor II; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase