IGF-1 Induces Pin1 Expression in Promoting Cell Cycle S-phase Entry

J Cell Biochem. 2002;84(2):211-6. doi: 10.1002/jcb.10037.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cyclin D1 / metabolism
  • Humans
  • Insulin-Like Growth Factor I / physiology*
  • MAP Kinase Signaling System
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Peptidylprolyl Isomerase / biosynthesis
  • Peptidylprolyl Isomerase / genetics
  • Peptidylprolyl Isomerase / physiology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Retinoblastoma Protein / metabolism
  • S Phase / physiology*
  • Tumor Cells, Cultured
  • Up-Regulation / physiology

Substances

  • NIMA-Interacting Peptidylprolyl Isomerase
  • Retinoblastoma Protein
  • Cyclin D1
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • PIN1 protein, human
  • Peptidylprolyl Isomerase
  • Pin1 protein, mouse