期刊
CELL DEATH AND DIFFERENTIATION
卷 8, 期 1, 页码 16-29出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4400762
关键词
IGF-II; transgenic mice; mammary involution; apoptosis; Akt/PKB
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-11 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 lobuto-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.
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