Negative regulation of the Wnt-β-catenin pathway by the transcriptional repressor HBP1

In certain cancers, constitutive Wnt signaling results from mutation in one or more pathway components. The result is the accumulation and nuclear localization of beta -catenin, which interacts with the lymphoid enhancer factor-1 (LEF)/T-cell factor (TCF) family of HMG-box transcription factors, which activate important growth regulatory genes, including cyclin DI and c-myc. As exemplified by APC and axin, the negative regulation of beta -catenin is important for tumor suppression. Another potential mode of negative regulation is transcriptional repression of cyclin DI and other Writ target genes. In mammals, the transcriptional repressors in the Wnt pathway are not well defined. We have previously identified HBP1 as an HMG-box repressor and a cell cycle inhibitor. Here, we show that HBP1 is a repressor of the cyclin DI gene and inhibits the Wnt signaling pathway. The inhibition of Writ signaling and growth requires a common domain of HBP1. The apparent mechanism is an inhibition of TCF/LEF DNA binding through a physical interaction with HBP1. These data suggest that the suppression of Wnt signaling by HBP1 may be a mechanism to prevent inappropriate proliferation.