TGF-β1 regulates cell fate during epithelial-mesenchymal transition by upregulating survivin

Cell Death Dis. 2013 Jul 4;4(7):e714. doi: 10.1038/cddis.2013.244.

Abstract

Members of the transforming growth factor beta (TGF-β) superfamily are multifunctional cytokines that regulate several cellular processes, including cell cycle arrest, differentiation, morphogenesis, and apoptosis. TGF-β promotes extracellular matrix production and morphological change. Morphogenetic responses to TGF-β include cell migration and epithelial-mesenchymal transition (EMT), which are critical during embryogenesis, development of fibrotic diseases, and the spreading of advanced carcinomas. The purpose of this study was to clarify how TGF-β regulates the fate of retinal pigment epithelial (RPE) cells. TGF-β1 promoted cell cycle progression and phosphorylation of retinoblastoma protein (Rb) in ARPE-19 cells. TGF-β1 induced survivin expression, which in turn stabilized tubulin and Aurora B. RT-PCR and western blot analysis revealed that survivin expression increased in ARPE-19 cells following TGF-β1 treatment. When survivin was depleted, TGF-β1 induced cell cycle arrest and apoptosis and also reduced Rb phosphorylation. In conclusion, the present study shows that induction of EMT in human RPE cells upregulates survivin, leading to survivin-dependent inhibition of cell cycle arrest and apoptosis. Whether cells undergo EMT or apoptosis in response to TGF-β1 is dependent on their cell cycle state, and TGF-β1 regulates the cell cycle via survivin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Aurora Kinase B / metabolism
  • Cell Line, Tumor
  • Cell Survival
  • Epithelial-Mesenchymal Transition*
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics*
  • Inhibitor of Apoptosis Proteins / metabolism
  • Mitosis
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Stability
  • Retinal Pigment Epithelium / physiology
  • Survivin
  • Transcriptional Activation*
  • Transforming Growth Factor beta1 / physiology*
  • Tubulin / metabolism
  • Up-Regulation

Substances

  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • Survivin
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • Tubulin
  • Phosphatidylinositol 3-Kinases
  • AURKB protein, human
  • Aurora Kinase B