Transcriptional Response Regulation

A second area of interest in my laboratory is to investigate how cells mediate the nuclear response to BMP signaling with particular emphasis on the role of Schnurri (Shn) in this process. Signaling is initiated when the dimeric BMP ligand forms a complex with type I and type II transmembrane serine-threonine kinase receptors. This interaction culminates in the phosphorylation of specific cytosolic proteins called R-Smads that translocate to the nucleus and can directly bind DNA to regulate transcription. However, Smads bind DNA with low affinity and recognize sequences of low complexity. Thus interactions with other transcription factors are necessary to provide pathway and/or promoter specificity. Our previous work identified the zinc finger protein Shn as one of the first Smad cofactors (Arora et al., 1995; Dai et al., 2000; Torres-Vazquez et al., 2000, 2001). Shn is an evolutionarily conserved protein with three homologs in humans, hShn1, hShn2 and hShn3. Currently we are investigating two different aspects of Shn function: (1) Are vertebrate Shn homologs also required to mediate BMP responsiveness? (2) Are the cis-regulatory elements in BMP responsive genes to which Shn-like proteins bind also conserved across species? We and our collaborators have uncovered evidence that minimal promoter fragments from BMP responsive genes in mouse and Xenopus can mediate a transcriptional response in Drosophila. Our identification of BMP-responsive cis-elements that are functionally conserved over such vast phylogenetic distances suggests an unexpected degree of similarity in the transcriptional mechanisms involved in the response to BMP ligands (Brugger et al., 2004; Yao et al., 2006).

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