Professor, Biochemistry and Molecular Genetics
- BS, Genetics, University of York, England
- PhD, Genetics, Imperial Cancer Research Fund, London
Center for Cell Signaling, Hospital West
HSC 800577, Rm #7008 (office), Rm# 7161 (lab)
Charlottesville, VA 22908
Biochemistry, Cancer Biology, Cell and Developmental Biology, Epigenetics, Genetics, Metabolism, Molecular Biology
Regulation of Gene Expression, Development and Tumor Progression by TGF beta Signaling
Analysis of the role of TGIFs during development.
TGIF proteins are transcriptional repressors, which regulate TGFβ signaling and have been suggested to repress retinoid regulated gene expression. Mutations in human TGIF are associated with holoprosencephaly (HPE), suggesting an important role in brain development and craniofacial morphogenesis. We have knocked out both Tgif1 and Tgif2 in mice and are analyzing defects in single and double mutant mice. We have shown that Tgif1;Tgif2 conditional double mutant mice develop HPE that is dependent on disruption of Sonic Hedgehog (Shh) signaling. We are currently analyzing the mechanisms by which loss of Tgifs and increased Nodal signaling affect the Shh pathway, cause HPE and regulate other early developmental processes.
Molecular analysis of transcriptional repression by TGIFs.
We are analyzing the role that Tgifs play in regulating TGFβ activated gene expression and identifying target genes using transcriptome profiling by RNA-seq, from both embryos and cultured cells. In addition, we have begun to examine transcriptional repression by Tgifs via pathways other than TGFβ signaling. We have shown that Tgif1 represses gene expression via certain nuclear receptors, and have also identified a class of neural zinc finger transcription factors with which Tgif1 interacts. We are now actively trying to understand the importance of this interaction for neural development and differentiation. One interesting possibility that we are testing is that this link between Tgifs and neural zinc finger factors plays a role in the development of glioblastoma.
Analysis of the role of TGFβ signaling during prostate cancer progression.
Prostate cancer is the second leading cause of deaths due to cancer in North American men. We are testing how mutations in genes that are commonly found to be mutated in human prostate cancer cooperate to drive local prostate tumors to high grade invasive cancer. We have developed a novel prostate cancer mouse model, based on mutations in the Pten and Tgfbr2 tumor suppressor genes. We will determine how mutation of the Tgfbr2 gene allows primary tumors to become invasive and metastatic, and will use this model to test the efficacy of common therapeutic approaches to human prostate cancer. Additionally, we are exploring the pathways that are regulated by TGFβ in prostate that contribute to prostate cancer progression when the pathway is disrupted. Finally we are trying to generate better mouse models of prostate cancer that will better allow us to study metastasis.