Moorehead R A, Fata J E, Johnson M B, Khokha R
Department of Medical Biophysics, Ontario Cancer Institute/University Health Network, University of Toronto, Toronto, Ontario, M5G 2M9, Canada.
Cell Death Differ. 2001 Jan;8(1):16-29. doi: 10.1038/sj.cdd.4400762.
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
胰岛素样生长因子-II（IGF-II）是一种与人类癌症和动物肿瘤模型相关的生长因子。虽然IGF-II的促有丝分裂特性已有充分记载，但其在体内抑制细胞凋亡的能力从未得到证实。我们培育了独立的MMTV-IGF-II转基因小鼠，以研究在哺乳期后乳腺退化这一生理过程中，上皮细胞凋亡在形态学、细胞水平和分子水平上的调控情况。在乳腺上皮中实现了转基因IGF-II的表达，并且通过胰岛素受体底物-1（I型IGF受体下游的信号分子）的磷酸化证实了IGF-II生物活性的增加。IGF-II的过表达导致乳腺退化延迟，这表现为乳腺与体重之比增加，以及功能完整的小叶腺泡和乳腺上皮细胞的持续存在。乳腺退化延迟是由于乳腺上皮细胞凋亡显著减少，而非上皮细胞增殖增加所致。将重组IGF-II微丸植入野生型小鼠退化的乳腺中，进一步证明了IGF-II蛋白可抑制局部上皮细胞凋亡。在分子水平上，磷酸化的Akt/PKB（而非Erk1或Erk2）在IGF-II过表达小鼠中持续存在，并且在时间上与上皮细胞凋亡减少相关。转基因组织中磷酸酶PTEN的水平未发生改变，这表明Akt/PKB磷酸化的维持是由于持续的磷酸化而非PIP-3去磷酸化的改变。总之，这些数据表明IGF-II在体内抑制细胞凋亡，并且这种作用与Akt/PKB的长期磷酸化相关。
