The goals of Project Retinoid-Receptor Interactions are united by the theme of elucidating the molecular mechanisms of retinoid action in breast cancer cells to identify more effective therapeutic agents to treat this devastating disease. Retinoids have profound effects on cell differentiation, homeostasis, and vertebrate development and are clinically useful in the treatment of several types of cancer and dermatological diseases. The two classes of nuclear retinoid receptors retinoic acid (RAR) and retinoid X (RXR) receptors mediate their pleiotropic effects of cell function by acting as ligand-dependent transcription factors in the form of RXR/RAR heterodimers to regulate the expression of retinoid target genes. Ligand-induced alterations of retinoid receptor conformation have roles as molecular switches that covert transcriptionally inactive receptors into complexes that interact productively (activate) or inhibit (repress) the transcriptional machinery or antagonize transcriptional activation mediated by AP-1 all functions with modulate the antiproliferative effects of retinoids. These responses appear to be involve the interaction of retinoid receptors with other cellular proteins known as transcriptional intermediary factors, which function as co-activators or co-repressor. Because of the central role of retinoid(s) in these processes, an understanding of ligand interactions with retinoid receptors and the structural alterations in the receptors that occur as a result of ligand binding is of critical importance. The goal of Aim III.1 is to map retinoid receptor regions that undergo structural alteration as a consequence of ligand (agonist and antagonist) binding using the techniques of limited proteolysis and mass spectrometry. Expression of the retinoic acid receptor beta2 (RARbeta2) gene is regulated by retinoid receptor complexes in a ligamd=de[ememt manner. The RARbeta2 protein has been implicated in breast cancer cell growth inhibition and apoptosis. The goal of Aim III.2 is to develop an in vitro transcription system in which regulation of the RARbeta2 promoter can be studied to determine the mechanism(s) by which liganded retinoid receptors activate this promoter and the effect of other transcription factors, such as pEA3, on these regulatory processes. The synthetic retinoid 6-[3-(1-adamantyl)-4- hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN) induces breast cancer cell apoptosis through mechanism(s) independent of the RARs and RXRs. The goal of Aim III.3 is to purify the AHPN receptor and clone the cDNA encoding this protein to aid in the understanding of the mechanism of action of AHPN.
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