Cell cycle control is closely associated with cancer. Cell cycle progression from the G1 to S phase is governed by G1 cyclin-dependent kinases (CDKs), which include CDK4 (and the homologous CDK6) as well as CDK2. TGF-beta can potently inhibit cell cycle progression by causing cell cycle arrest at the G1 phase. Smad proteins can mediate the TGF-beta growth-inhibitory effects by regulating the expression of several cell cycle- related genes. For example, Smad proteins have been shown or implicated to upregulate the expression of CDK inhibitors p21 and p15, and downregulate the expression of the c-myc protooncogene. We have recently discovered that transfected or recombinant Smad3 can be potently phosphorylated by G1 CDKs, in particular, by CDK4/6. CDK phosphorylation can inhibit the basal as well as TGF-beta-induced transcriptional activity of Smad3. Smad2, which is homologous to Smad3 and has overlapping as well as distinct activities from Smad3, is also phosphorylated by G1 CDKs albeit not as extensively as Smad3. Our recent studies also suggest that Smad3 and Smad2 probably can inhibit cell growth. Based on these findings, we hypothesize that Smads can inhibit cell growth, and that CDK phosphorylation can suppress their activities, thus facilitating cell cycle progression and oncogenic transformation. The specific aims of this proposal include to demonstrate that endogenous Smad3 and Smad2 are phosphorylated by G1 CDKs, to determine how CDK phosphorylation affects their activities, and to investigate the role of Smad3 and Smad2 in cell growth regulation. We anticipate that the findings of this application will shed new insights into the mechanisms of tumorigenesis.
|Effective start/end date||12/14/01 → 11/30/07|
- National Cancer Institute: $279,529.00
- National Cancer Institute: $255,525.00
- National Cancer Institute: $249,432.00
- National Cancer Institute: $255,612.00
- National Cancer Institute: $255,697.00
- Cell Biology
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.