Molecular mechanisms of inactivation of TGF-beta receptors during carcinogenesis.
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.
Kim
S J
SJ
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD 20892-5055, USA. kims@dce41.nci.nih.gov
Im
Y H
YH
Markowitz
S D
SD
Bang
Y J
YJ
D030201:Activin Receptors, Type I; D000818:Animals; D020868:Gene Silencing; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic
D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II