IGF-1 induces Pin1 expression in promoting cell cycle S-phase entry.

TitleIGF-1 induces Pin1 expression in promoting cell cycle S-phase entry.
Publication TypeJournal Article
Year of Publication2002
AuthorsYou H, Zheng H, Murray SA, Yu Q, Uchida T, Fan D, Xiao Z-XJim
JournalJ Cell Biochem
Date Published2002
KeywordsCyclin D1, Humans, Insulin-Like Growth Factor I, MAP Kinase Signaling System, NIMA-Interacting Peptidylprolyl Isomerase, Peptidylprolyl Isomerase, Phosphatidylinositol 3-Kinases, Phosphorylation, Retinoblastoma Protein, S Phase, Tumor Cells, Cultured, Up-Regulation

Insulin-like growth factor I (IGF-1) is a well-established mitogen to many different cell types and is implicated in progression of a number of human cancers, notably breast cancer. The prolyl isomerase Pin1 plays an important role in cell cycle regulation through its specific interaction with proteins that are phosphorylated at Ser/Thr-Pro motifs. Pin1 knockout mice appear to have relatively normal development yet the Pin1(-/-)mouse embryo fibroblast (MEF) cells are defective in re-entering cell cycle in response to serum stimulation after G0 arrest. Here, we report that Pin1(-/-) MEF cells display a delayed cell cycle S-phase entry in response to IGF stimulation and that IGF-1 induces Pin1 protein expression which correlates with the induction of cyclin D1 and RB phosphorylation in human breast cancer cells. The induction of Pin1 by IGF-1 is mediated via the phosphatidylinositol 3-kinase as well as the MAP kinase pathways. Treatment of PI3K inhibitor LY294002 and the MAP kinase inhibitor PD098059, but not p38 inhibitor SB203580, effectively blocks IGF-1-induced upregulation of Pin1, cyclin D1 and RB phosphorylation. Furthermore, we found that Cyclin D1 expression and RB phosphorylation are dramatically decreased in Pin1(-/-) MEF cells. Reintroducing a recombinant adenovirus encoding Pin1 into Pin1(-/-) MEF cells restores the expression of cyclin D1 and RB phosphorylation. Thus, these data suggest that the mitogenic function of IGF-1 is at least partially linked to the induction of Pin1, which in turn stimulates cyclin D1 expression and RB phosphorylation, therefore contributing to G0/G1-S transition.

Alternate JournalJ Cell Biochem
PubMed ID11787050
Grant ListCA79804 / CA / NCI NIH HHS / United States
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