Molecular mechanisms of inactivation of TGF-beta receptors during carcinogenesis

Cytokine Growth Factor Rev. Mar-Jun 2000;11(1-2):159-68. doi: 10.1016/s1359-6101(99)00039-8.

Abstract

Signals from the TGF-betas are mediated by the TGF-beta receptors and their substrates, the Smad proteins. Inactivation of either of the two transmembrane serine/threonine kinases called the TGF-beta type I and type II receptors is now known to underlie a wide variety of human pathologies including, especially carcinogenesis. Numerous studies have now demonstrated that the TGF-beta receptor complex and its downstream signaling intermediates constitute a tumor suppressor pathway. We review here a specific pathway of mutational inactivation of the TGF-beta type II receptor resulting from microsatellite instability and demonstrate that, by contrast, the most common mechanism of loss of expression of the TGF-beta type II receptor involves transcriptional repression. This provides a new target for therapeutic intervention.

Publication types

  • Review

MeSH terms

  • Activin Receptors, Type I*
  • Animals
  • Gene Silencing
  • Humans
  • Mutation
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics*
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Transcription, Genetic

Substances

  • Receptors, Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II