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Published on: June 17, 2014
Negative regulation of the Wnt-beta-catenin pathway by the transcriptional repressor HBP1
E M Sampson1, Z K Haque, M C Ku
1Department of Biochemistry, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
Abstract:
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 D1 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 D1 and other Wnt 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 D1 gene and inhibits the Wnt signaling pathway. The inhibition of Wnt 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.
Insights
HBP1 protein suppresses Wnt signaling by inhibiting lymphoid enhancer factor-1 (LEF)/T-cell factor (TCF) DNA binding. This Wnt pathway inhibition by HBP1 may prevent uncontrolled cell proliferation in cancer.
Area of Science:
- Molecular Biology
- Cancer Biology
- Cell Signaling
Background:
- Constitutive Wnt signaling, driven by mutations, leads to beta-catenin accumulation and nuclear localization in cancer.
- Beta-catenin interacts with lymphoid enhancer factor-1 (LEF)/T-cell factor (TCF) transcription factors, activating genes like cyclin D1 and c-myc.
- Negative regulation of beta-catenin and Wnt target genes is crucial for tumor suppression, but mammalian repressors are not well-defined.
Purpose of the Study:
- To investigate the role of HBP1, a previously identified HMG-box repressor, in the Wnt signaling pathway.
- To determine if HBP1 acts as a repressor of Wnt target genes, specifically cyclin D1.
- To elucidate the mechanism by which HBP1 inhibits Wnt signaling.
Main Methods:
- Assessed HBP1's function as a repressor of the cyclin D1 gene.
- Evaluated HBP1's impact on Wnt signaling pathway activity.
- Investigated the functional domains of HBP1 required for Wnt inhibition.
- Examined the interaction between HBP1 and TCF/LEF transcription factors.
Main Results:
- HBP1 was confirmed as a repressor of the cyclin D1 gene.
- HBP1 was shown to inhibit the Wnt signaling pathway.
- A common domain within HBP1 is essential for both Wnt signaling and cell growth inhibition.
- HBP1 physically interacts with TCF/LEF, inhibiting their DNA binding activity.
Conclusions:
- HBP1 acts as a transcriptional repressor in the Wnt pathway.
- HBP1 inhibits Wnt signaling by blocking TCF/LEF-mediated DNA binding.
- Suppression of Wnt signaling by HBP1 represents a potential mechanism against inappropriate cell proliferation in cancer.
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