Insulin-like growth factor I triggers nuclear accumulation of cyclin D1 in MCF-7S breast cancer cells.
Stimulation of the breast cancer-derived MCF-7S cell line with insulin-like growth factor I (IGF-I; 20 ng/ml) leads to enhanced expression of cyclin D1, hyperphosphorylation of pRb, DNA synthesis, and cell division. 17beta-Estradiol (E(2); 10(-9) m) is not able to stimulate proliferation of MCF-7S cells, although addition of E(2) to serum-starved cells does result in induction of cyclin D1. However, in combination with submitogenic amounts of IGF-I (2 ng/ml), E(2) induces cell proliferation. We have previously shown that the synergistic action of E(2) and IGF-I emanates from the ability of both hormones to induce cyclin D1 expression and that IGF-I action is required to induce activity of the cyclin D1-CDK4 complex, which triggers cell cycle progression. Here, we show that IGF-I (but not E(2)) is able to induce nuclear accumulation of cyclin D1 by a phosphatidylinositol 3-kinase-dependent mechanism. Nuclear accumulation of cyclin D1 and cell cycle progression were also observed when LiCl, a known inhibitor of GSK3beta, was added to E(2)-stimulated cells. Thus, inhibition of GSK3beta activity appears to trigger nuclear accumulation of cyclin D1 and cell cycle progression. This notion was confirmed by overexpression of constitutively active GSK3beta, which blocks IGF-I-induced nuclear accumulation of cyclin D1 as well as S phase transition.
D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D016193:G1 Phase; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D018021:Lithium Chloride / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D016196:S Phase; D014162:Transfection; D014407:Tumor Cells, Cultured
D042846:CDC2-CDC28 Kinases; D019938:Cyclin D1; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D004958:Estradiol; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D007334:Insulin-Like Growth Factor I; D018021:Lithium Chloride; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; C000605506:GSK3B protein, human; C495894:CDK2 protein, human