Mechanism of cell cycle regulation by FIP200 in human breast cancer cells. | Academic Article individual record
abstract

FIP200 is a novel protein inhibitor for focal adhesion kinase (FAK), which binds to FAK directly and inhibits its kinase activity and associated cellular functions, such as cell adhesion, spreading, and motility in fibroblasts. Here we show that FIP200 inhibits G1-S phase progression, proliferation, and clonogenic survival in human breast cancer cells. Consistent with the G1 arrest induced by FIP200, we found that FIP200 increased p21 and decreased cyclin D1 protein levels in breast cancer cells. In addition, FIP200 significantly induced p21 promoter activity in MCF-7 cells and this response was abolished upon deletion of p53 binding sites within p21 promoter. Furthermore, we found that FIP200 could interact with exogenous and endogenous p53 protein and significantly increase its half-life compared with the control cells. We also found that the NH2-terminal 154 residues of FIP200 were sufficient to mediate p53 interaction and G1 arrest in cells. The increase in p53 half-life correlated with the increased phosphorylation at Ser15 and decreased proteasomal degradation via ubiquitin and Hdm2-independent mechanism. Stabilization of p53 by FIP200 could be partially reversed by NQO1 inhibitor, dicoumarol. In contrast to p53, FIP200 decreased cyclin D1 protein half-life by promoting proteasome-dependent degradation of cyclin D1. In summary, our results suggest that FIP200 increases p21 protein levels via stabilization of its upstream regulator p53 and decreases cyclin D1 protein by promoting its degradation. Both effects are critical for FIP200-induced G1 arrest and may contribute to the putative antitumor activities of FIP200 in breast cancer.

authors
author list (cited authors)
Melkoumian, Z. K., Peng, X. u., Gan, B., Wu, X., & Guan, J.
publication date
2005
published in
keywords
  • Transfection
  • Humans
  • Protein-Tyrosine Kinases
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor P21
  • Cell Cycle Proteins
  • Proteasome Endopeptidase Complex
  • Up-Regulation
  • G1 Phase
  • Phosphorylation
  • Breast Neoplasms
  • Cell Cycle
  • Cyclin D1
  • Tumor Suppressor Protein P53