Human Cut-Like Repressor Protein Binds TGFβ Type II Receptor Gene Promoter

Resistance to the growth inhibitory effects of transforming growth factor β (TGFβ) has been associated with decreased levels of the TGFβ type II receptor (TβR-II) and has been correlated with tumorigenicity. Previously, we reported an A → G mutation at position −364 in the TβR-II promoter in A431 tumor cells which results in reduced TβR-II promoter activity. In this study, we show that the CDP/Cut (CCAAT displacement protein) transcription factor, a transcriptional repressor, binds both the wild type and the mutant TβR-II promoter. We also demonstrate that the A → G mutation increases CDP/Cut binding affinity, and that overexpression of CDP/Cut reduces transcription from TβR-II promoter reporter constructs. Increased binding of the CDP/Cut repressor protein, as a result of a mutation at position −364, represents a novel mechanism of regulation in a neoplastic cell of the promoter of a tumor suppressor gene, TβR-II.