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IGF‐1 induces Pin1 expression in promoting cell cycle S‐phase entry
Author(s) -
You Han,
Zheng Hongwu,
Murray Steven A.,
Yu Qiang,
Uchida Takafumi,
Fan Daiming,
Xiao ZhiXiong Jim
Publication year - 2001
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.10037
Subject(s) - pin1 , cyclin d1 , cell cycle , cyclin d , biology , phosphorylation , cyclin , microbiology and biotechnology , cyclin e , cyclin a , cancer research , kinase , cyclin dependent kinase 2 , protein kinase a , cell , biochemistry , isomerase , gene
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. J. Cell. Biochem. 84: 211–216, 2002. © 2001 Wiley‐Liss, Inc.