Functional Analysis of the Transcriptional Co-Activator CBP in Wnt-Signaling Dependent
Final rept. 17 Apr 2000-16 Apr 2003
DUKE UNIV MEDICAL CENTER DURHAM NC
Pagination or Media Count:
Wnt signaling is mediated by a multi-components cascade that relays the signal from cell membrane to nuclear TCF-BETA- catenin transcriptional complex. Genetic study has implicated CREB-Binding Protein CEP as a negative regulator of Wnt signaling. We initially found that CBP can acetylate TCF4, the key transcriptional effector in the wnt signaling pathway. Furthermore, we also found that CBP and beta-catenin, another key element of the wnt signaling, forms a complex. We proposed that that CBP-mediated acetylation negatively regulates TCF-dependent transcription in the absence of Wnt signaling. Wnt signaling then relieves this repression and converts CBP to a classical transcriptional-coactivator by inducing its complex formation with beta-catenin. Supporting this possibility, by analyzing TCF reporters integrated chromosomally, we have obtained evidence that TCF binding sites indeed confer transcriptional repression activity. Furthermore, we have found that CBP potentiates TCF-beta-catenin transcriptional activity in a reporter assay. However, whether or not acetylation of TCF plays a critical role in establishing the repression remains to be established, as we have evidence that there are more than one acetylation sites present in TCF4. The identification of the novel acetylation sites, which is still being pursued in the lab, will be critical for analyzing the function of TCF acetylation and how CBP regulates Wnt signaling.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology