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News, Calendars, and Events » Calendars » Master Calendar » Biochemistry and Molecular & Cellular Biology, Department of
Seminar Series: Dr. Kenneth Michael Cadigan
Schedule information
Event Seminar Series: Dr. Kenneth Michael Cadigan
When Tuesday, January 8, 2013 from 12:00pm to 1:00pm
Where Basic Science Building 341 (Library)
Event details
Details Finding a Needle in a Genetic Haystack: How do TCFs Mediate Wnt signaling in Metazoans?

Dr. Kenneth Michael Cadigan
Professor of Molecular, Cellular and Developmental Biology
University of Michigan

Abstract: Wnt/beta-catenin signaling plays many important roles in cell specification during development and in adult tissue homeostasis. This signaling cascade, found throughout metazoa, functions by increasing the nuclear concentration of b-catenin, which acts as a transcriptional co-regulator. T-cell factors (TCFs) are the best understood family of transcription factors that recruit b-catenin to Wnt target genes. All TCFs contain a High Mobility Group (HMG) domain, which possesses specific DNA-binding activity. However there is considerable degeneracy in HMG-DNA recognition, such that HMG binding sites are found at high frequency throughout the genome. Yet the available data indicates that only a small portion of these predicted sites function in Wnt response elements (WREs, cis-regulatory modules that regulate transcription in a Wnt dependent manner). In Drosophila, we have found that Pangolin (Pan, the fly TCF) contains a second DNA-binding domain, the C-clamp, which recognizes a sequence motif we call the Helper site. Our data in flies and C. elegans indicate that both HMG and Helper sites are essential to specify WREs. We are using this information to improve our ability to identify additional WREs computationally, and to explore how the quality of TCF binding sites affects the transcriptional output in developmental contexts.

In contrast to invertebrates, most vertebrate TCFs do not contain C-clamps. We are characterizing several vertebrate WREs, and have found no evidence for obligatory sequence motifs near functional HMG binding sites. Rather, we have evidence for a “Helper by committee” model, where clusters of transcription factor binding sites work together with HMG sites to mediate Wnt-dependent transcriptional activation. We are currently attempting to understand how this process operates mechanistically.

In addition to activating WREs, there are a few cases where TCFs and beta-catenin directly repress transcription of target genes. We have identified a novel class of HMG and Helper sites in repressed WREs, which allosterically regulate TCF/beta-catenin transcriptional output. Support for this model comes from experiments where we have converted repressed WREs to activated ones (and vice versa) simply by altering the sequence of the TCF binding sites.
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Contact Juanita Chipani Biochemistry and Molecular & Cellular Biology office, x71512
Sponsors Department of Biochemistry and Molecular & Cellular Biology
Calendar Biochemistry and Molecular & Cellular Biology, Department of
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