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Dr. Talmage's laboratory is interested in the interactions between retinoids and receptor tyrosine kinase signaling pathways. Currently his laboratory is focusing on three research areas: 1) To determine how retinoids inhibit the progression of early neoplastic lesions. Vitamin A metabolites (retinoids) limit oncogenesis by regulating genes whose products control proliferation, differentiation and apoptosis. His fundamental hypothesis has been that retinoids control many diverse biological responses by regulating the expression of genes whose products regulate signal transduction, and therefore the target cell's ability to respond to environmental cues; 2) To understand how target cell retinoid status is regulated and how normal retinoid status is lost during oncogenesis. Tumor development is accompanied by loss of expression of retinoid-regulated genes and loss of responsiveness to exogenous retinoids. His laboratory has demonstrated that expression of retinoid regulated genes is normally under endocrine control in sex steroid responsive tissues, and further that activated tyrosine kinases inhibit RARα function; 3) To understand the function of specific isoforms of the Nrg1 gene. Many human breast cancers express elevated levels and/or constitutively active receptors of the EGF receptor family, in particular ErbB2 and ErbB3. In collaboration with Dr. L. Role, he has initiated three sets of experiments. In one, they have demonstrated Nrg1 isoforms that differ at their N-termini differentially activate and signal through various combinations of ErbB receptors. Second, they have demonstrated that the cytoplasmic domain of Nrg1, upon induced cleavage and release of the extracellular growth factor domain enters the nucleus where it regulates gene expression. Thus, Nrg1 acts both on target, ErbB expressing cells, and as a signaling molecule in Nrg1 expressing cells. Third, mice with a disruption that specifically targets the 5'-exon of type III Nrg1 isoforms have been generated. These mice are being used to look for deficits in specific ErbB activated protein kinase signaling pathways. Talmage DA, Role LW. Multiple personalities of neuregulin gene family members J Comp Neurology 472:134-139, 2004. Bao J, Wolpowitz D, Role LW, Talmage DA. Back-signaling by the Nrg-1 intracellular domain. J Cell Biology 161:1133-1141, 2003. Cho, Y. Talmage, D.A. Protein kinase C α expression confers retinoic acid sensitivity in MDA-MB-231 human breast cancer cells. Expt Cell Research 269:97-108, 2001. |
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David A. Talmage, Ph.D., Associate Professor of Clinical Nutrition