Accession Number:

ADA394048

Title:

Functional Analysis of the Transcriptional Co-Activator CBP in Wnt-Signaling Dependent

Descriptive Note:

Annual rept. 17 Apr 2000-16 Apr 2001

Corporate Author:

DUKE UNIV MEDICAL CENTER DURHAM NC

Personal Author(s):

Report Date:

2001-05-01

Pagination or Media Count:

11.0

Abstract:

Wnt signaling is mediated by a multi-component cascade that relays the signal from cell membrane to nuclear TCF-beta-catenin transcriptional complex and thereby, modulates gene expression. Gain of function mutations in the Wnt pathway lead to various cancers. Genetic study has implicated CREB-Binding Protein CBP as a negative regulator of Wnt signaling, suggesting that CBP could modulate the Wnt-induced carcinogenesis. In the current study, we examined the functional relationship between CBP and Wnt-dependent transcription mediated by TCF-beta-catenin. Unexpectedly, we found that CBP does not negatively regulate TCF-beta-catenin-mediated transcription. Instead, CBP potentiates TCF-beta- catenin transcriptional activity by physically interacting with beta-catenin. Our results have two implications. First, as CBP is a known transcriptional co-activator, the beta-catenin-CBP interaction provides a mechanism to explain how recruitment of beta- catenin activates TCF transcriptional activity. Second, it suggests a possibility that beta-catenin might function as a molecular switch that modulates the activity of CBP toward TCF-dependent transcription events. We hypothesize that in the absence of beta-catenin, CBP facilitates the function of TCF as a transcriptional repressor. Upon binding to beta-catenin, CBP is converted to a classical transcriptional co-activator and forms a TCF-beta-catenin-CBP complex that activates Wnt-dependent downstream target genes.

Subject Categories:

  • Biochemistry
  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE