| KLF6 is a tumor suppressor gene that is inactivated in a majority of sporadic prostate and colon cancers. One mechanism of growth suppression by KLF6 is via its transcriptional up-regulation of p21WAF1/Cp1.; Here, we have identified two additional mechanisms of growth regulation by KLF6. The first is mediated through its direct protein-protein interaction with cyclin D1, which results in reduced phosphorylation of the retinoblastoma protein Rb at Serine-795 (S795)—a specific substrate of the cyclin D1/cdk4 complex. This mechanism is further substantiated by evidence that inactivation of KLF6, either following the expression of tumor-derived mutants or silencing of the endogenous gene by siRNA, results in increased Rb phosphorylation at this site. The second mechanism involves transcriptional repression of the cyclin D1 promoter by KLF6, identifying transcriptional repression—aside from transactivation—as an additional biological activity of the tumor suppressor KLF6.; These results suggest that KLF6 converges with the Rb pathway to bifunctionally inhibit cyclin D1 activity via its role as a cyclin-dependent kinase inhibitor (CKI) and its transcriptional repression of the cyclin D1 gene. Thus, we hypothesize that the tumor suppressor protein KLF6 has a role in cell cycle control, the outcome of which is the inhibition of cell proliferation. |
