title: IGF-1 induces Pin1 expression in promoting cell cycle S-phase entry.
abstract: 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.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Han
authors.initials: H
authors.lastname: You
authors.forename: Hongwu
authors.initials: H
authors.lastname: Zheng
authors.forename: Steven A
authors.initials: SA
authors.lastname: Murray
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yu
authors.forename: Takafumi
authors.initials: T
authors.lastname: Uchida
authors.forename: Daiming
authors.initials: D
authors.lastname: Fan
authors.forename: Zhi-Xiong Jim
authors.initials: ZX
authors.lastname: Xiao
mesh_terms: D019938:Cyclin D1 / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D020935:MAP Kinase Signaling System; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000502:physiology
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse