description) Extracellular matrix (ECM) effects on gene regulatory events are hypothesized to occur, in part, through a direct effect on the nuclear matrix. The role of the ECM in several biological processes is now well established and much is known about the multiple signaling pathways that are activated by ECM interactions with the integrin family of cell surface receptors. The point of contact between the ECM and integrins occurs at specialized structures termed focal adhesions. While various second messenger systems mobilized at focal adhesion may be used to transmit ECM-directed signals to changes in gene expression, there also appears to be a """"""""physical"""""""" link between the ECM and the nuclear matrix. This application presents evidence that HIV-5 (hydrogen peroxide-inducible clone-5), a protein associated with focal adhesions, acts to potentiate glucocorticoid receptor transactivation. Furthermore, HIC-5 does not appear to be restricted to focal adhesions, as a fraction has been localized to the nuclear matrix. Finally, LIM domains of Hic-5 were found to interact with a transactivation domain of the glucocorticoid receptor ( i.e. GR. tau2) that encodes a nuclear matrix-targeting signal. The four Specific Aims that will be pursued in this application are as follows: 1) To identify amino acids within the GR.tau2 domain that are required for Hic-5 interaction, 2) To map functional domains of Hic-5 that influence GR transactivation, 3) To identify the mechanism of Hic-5 potentiation of GR transactivation, and 4) To examine whether Hic-5 participates in ECM regulation of GR function. Cellular responses to ECM clearly play a role in physiologically relevant steroid hormone responses in specific target tissues. Furthermore, alteration in focal adhesion protein function (e.g. paxillin) has been detected in metastatic prostate cancer. Thus the mechanistic analysis of LIM domain protein involvement in steroid receptor subnuclear trafficking and transactivation proposed in this application could increase our understanding of how cell attachment to the ECM influences gene expression both during normal development and in pathophysiological conditions.
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