EXCEED THE SPACEPROVIDED.Development of neurons, such as those of the endocrine hypothalamus invoves regulation by the actions ofnuclear receptors and by other classes of transcription factors, such as the Class III POU domain factors, aswell as the actions of specific signaling molecules. The initial five years under this Merit Award have provento be our most productive and innovative cycle under this Grant. We have contributed a series ofdiscoveries concerning the molecular mechanisms by which nuclear receptors mediate gene repression andactivation events and that have established a new paradigm concerning the molecular mechanisms of generegulation. Our central theme in our laboratory under this grant has been to define the molecularmechanisms by which nuclear receptors, POU domain factors, and other classes of transcriptionfactorsfunction via recruitment of corepressors and coactivators, and to define a role for these factors inestablishing neuronal and other cellular phenotypes and in regulating function. We have identified novelmolecular mechanisms that regulate tissue- and cell type-specific proliferation and activation, and definedroles for corepressors in these events. We will investigate the molecular basis of action of components ofthe TBLR1/TBL1/GPS2/ HDAC3 complexes, investigating the potential roles of GPS2 as an inhibitor ofspecific protein kinases, and the roles of site-specific phosphorylation of N-CoR/TBLR1 and TBL1 in therequired recruitment of specific ubiquitin ligase 19S proteasome machinery using neuronal models. Therelationship of these factors to the actin-related complexes that may detect nuclear localization andalterations in chromatin structure will be defined
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