Research / Clinical
Summary
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Diseases/Research Topics
Basic Cell Biology, Signal Transduction
Our focus is signal transduction by cGMP- and cAMP-dependent protein kinases (G- and A-kinase). We previously correlated the cAMP-mediated inhibition of erythroleukemia cell differentiation with the ability of A-kinase to induce NF-6B (RelB/P50) complexes and prevent normal down-regulation of c-myb. Recently, we demonstrated that RelB/P50 expression is sufficient to block differentiation, because RelB/P50 bound to an intronic c-myb enhancer prevented the block to transcriptional elongation which is a prerequisite for normal hematopoietic cell. We continued our work on transcriptional regulation by NO/cGMP and found that transactivation of the human fos promoter by NO and cGMP requires the presence of G-kinase and guanylate cyclase (Idriss et al., J. Biol. Chem., 274:9489-9493, 1999).
We determined that type I and II G-kinase, which differ in their subcellular localization and movement, regulate the fos promoter through different mechanisms. We have identified the cAMP-response element-binding protein CREB as the major transcription factor mediating the effect of NO/cGMP/G-kinase on the fos promoter.
In a yeast two-hybrid search for G-kinase interacting proteins we isolated the general transcriptional regulator TFII-I which specifically interacts and co-localizes with G-kinase I and is phosphorylated in response to cGMP. We found that G-kinase mediates the growth-inhibitory effects of cGMP observed in different cell systems: G-kinase inhibits the Ras/MAP-kinase pathway by uncoupling Ras from Raf1 kinase (Suhasini et al., Mol. Cell. Biol., 18:6983-6994, 1998). We recently found cell type-specific activation of Rap1 by NO/cGMP and cAMP analogues which is independent of G-kinase or A-kinase suggesting direct regulation of RapGEFs by cyclic nucleotides. Many of the studies on transcriptional regulation by NO/cGMP and on regulation of the MAP-kinase pathway by cyclic nucleotides were performed in collaboration with Dr. Gerry Boss.
Keywords: signal transduction, nitric oxide, cGMP- and cAMP-dependent protein kinases, Ras-related proteins, MAP kinases, B-Raf, differentiation, proliferation, gene expression, transcription factors
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