TGF-beta-induced cell-cycle arrest through the p21(WAF1/CIP1)-G1 cyclin/Cdks-p130 pathway in gastric-carcinoma cells

Int J Cancer. 1999 Nov 12;83(4):512-7. doi: 10.1002/(sici)1097-0215(19991112)83:4<512::aid-ijc13>;2-z.


Transforming growth factor-beta1 (TGF-beta) inhibits cell-cycle progression of many types of cells by arresting them in G(1)/S phase through inhibition of the active cyclin-Cdk complexes that lead to inhibition of Rb phosphorylation. In gastric-cancer cells, SNU16, TGF-beta treatment induced enhanced expression of p21(WAF1/CIP1) (p21), which inhibited the kinase activity of cyclin-D- and cyclin-E-associated Cdks and blocked p130 phosphorylation. TGF-beta also enhanced the stability of p130, suggesting that hypophosphorylation of p130 and increased stability of p130 contribute to p130-mediated G(1) arrest in gastric-cancer cells. Our results demonstrate that p21 and p130 are major downstream targets of TGF-beta in gastric-cancer cells and that a p21-G(1) cyclin/Cdks-p130/E2F pathway mediates growth inhibition by TGF-beta in these cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma / metabolism*
  • Carcinoma / pathology
  • Cell Cycle / drug effects
  • Cyclin G
  • Cyclin G1
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / biosynthesis
  • Cyclins / genetics
  • Cyclins / metabolism*
  • Dose-Response Relationship, Drug
  • Flow Cytometry
  • G1 Phase / drug effects
  • Humans
  • Phosphoproteins / metabolism*
  • Phosphorylation / drug effects
  • Proteins*
  • Retinoblastoma Protein / metabolism
  • Retinoblastoma-Like Protein p130
  • Signal Transduction / drug effects
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology
  • Transforming Growth Factor beta / pharmacology*
  • Tumor Cells, Cultured
  • Tumor Stem Cell Assay
  • Up-Regulation / drug effects


  • CCNG1 protein, human
  • CDKN1A protein, human
  • Cyclin G
  • Cyclin G1
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Phosphoproteins
  • Proteins
  • RBL2 protein, human
  • Retinoblastoma Protein
  • Retinoblastoma-Like Protein p130
  • Transforming Growth Factor beta
  • Cyclin-Dependent Kinases