Inhibition of Smad antiproliferative function by CDK phosphorylation.
Rb family members were the only demonstrated substrates of CDK4 until it was shown recently that Smad3, which plays a key role in mediating TGF-beta antiproliferative responses, is phosphorylated by both CDK4 and CDK2 in vivo and in vitro. CDK phosphorylation of Smad3 inhibits its transcriptional activity and antiproliferative function. The Rb pathway is disrupted in almost all human cancers. Most cancers contain high levels of CDK activity due to frequent inactivation of the p16 tumor suppressor or overexpression of cyclin D1. Therefore, disruption of the Rb pathway not only inactivates Rb, but also likely diminishes Smad activity, which may contribute to tumorigenesis and resistance to the TGF-beta growth-inhibitory effects in cancers. Although genetic mutation of Smad3 has not been reported, CDK phosphorylation of Smad3 may provide an epigenetic mechanism for inhibition of the tumor suppressive function of Smad3 during the early stages of tumorigenesis.
Liu
Fang
F
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, State University of New Jersey, Piscataway, New Jersey 08854, USA. fangliu@cabm.rutgers.edu
Matsuura
Isao
I
D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000502:physiology; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000235:genetics / Q000502:physiology; D051900:Smad3 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology
D016160:Retinoblastoma Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D018844:Cyclin-Dependent Kinases