Research / Clinical
Summary
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Gourisankar Ghosh, PhD
Professor, Chemistry & Biochemistry
Tumor Growth, Invasion & Metastasis Program
Contact by Email
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Diseases/Research Topics
Gene Regulation
Our research focuses primarily on the detailed mechanisms of signaling pathways that lead to the regulation of gene expression by nuclear factor kB (NF-kB). We have recently initiated a second project that aims to understand mRNA processing and transport. The foundation of our research rests upon high resolution x-ray structures of proteins and protein complexes. Hypotheses derived from these three dimensional structures are tested through biochemical and biological experiments to provide greater functional understanding of these important regulatory processes.
In most cells NF-k B dimers are retained in the cytoplasm due to their association with a family of inhibitor proteins called the I kBs. Various stimuli trigger a series of phosphorylation reactions that ultimately activate specific Ik B kinase complexes (IKKs). Phospho-I kB is degraded by the ubiquitin-linked proteasome pathway, resulting in free Rel/NF-kB dimers. These dimers then translocate to the nucleus and bind to specific DNA targets to induce transcription. Involvement of multiple family members of NF-kB, IkB and IKK in a differential manner adds complexity to this signaling pathway. We are interested in determining the mechanism of a) NF-kB dimer formation, b) regulation of NF-k B by Ik Bs, c) IKK regulation, d) ubiquitination of IkBs and e) transcriptional regulation by NF-kB.
Serine/arginine rich proteins (SR proteins) are essential for pre-messenger RNA processing and possibly for mRNA transport from the nucleus to the cytoplasm. SR proteins are modular in nature, containing an N-terminal RNA binding domain and C-terminal domain rich in SR/RS dipeptides. Phosphorylation of the serines of the RS dipeptides is essential for splicing and transport activities of the SR proteins. A novel class of kinases known as SR protein kinases (SRPKs) specifically phosphorylate these serines. We are interested in structure/function studies of the SR proteins and SRPKs in both yeast and mammalian systems.
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SELECTED PUBLICATIONS
The Crystal Structure of Ik Ba /NF-k B Complex Reveals Inhibition of NF- kB Functions. With T. Huxford, D-B. Huang, and S. Malek. Cell 95, 759 (1998).
Characterization of the Dimer Interface of Transcription Factor NF-kB p50 Homodimer. With L.L. Sengchanthalangsy, S. Dutta, D-B. Huang, E. Anderson, and E.H. Braswell. J. Mol. Biol. 289, 1029 (1999).
NF-kB p65 Uses d Distinct Sets of Residues to Recognize Different DNA Targets. With Y-Q. Chen, L.L. Sengchanthalangsy, and A. Hackett. Structure 8, 419 (2000).
The Mechanism of the DNA-binding by Rel/NF-kB Dimers. With C. Phelps, S. Malek, and L.L. Sengchanthalangsy. J. Biol. Chem. 275, 24392 (2000).
Mechanism of Ik Ba Binding by NF- kB Dimers. With C. Phelps, L.L. Sengchanthalangsy, and T. Huxford. J. Biol. Chem. 275, 29840 (2000).
PPARg -independent Mechanisms for inhibition of NF-k B and Prostaglandin Synthesis by 15-deoxy-delta12, 14- prostaglandin J2. With D.S. Straus, G. Pascual, M. Li, J.S. Welch, M. Ricote, L.L. Sengchanthalangsy, and C.K. Glass. Proc. Natl. Acad. Sci. USA 97, 4844 (2000).
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