Steroid receptors are members of the nuclear receptor superfamily of transcriptional that bind to specific DNA sequences to alter rates of gene transcriptional. How nuclear receptors gene transcription in vivo and response to hormone remains an essential question. The recent discovery of a multitude of proteins that interact with hormone activated receptors has provided important new insights into this question. Proteins have been identified that influence receptor-DNA interactions, act as co-adaptors """"""""or bridging proteins"""""""" between receptor and the general transcriptional machinery, and facilitate receptor- targeted chromatin modeling. Coordinated interactions between these various proteins clearly plays an essential role in mediating the transcriptional activity of receptors in response to hormonal signals. This research proposal will focus on one of these ancillary proteins, the chromatin high mobility group protein-1 (HMG-1) and closely related HMG-2, that we have identified as potentially important co-regulatory proteins for the steroid hormone class of nuclear receptors. HMG-1/-2 markedly enhance the sequence specific DNA binding activity and transcriptional activity in vivo (whole cells) of all steroid receptors, but none of the non-steroid class II nuclear receptor tested. Studies are proposed to determine the role of HMG-1/-2 in steroid receptor function in vivo, its mechanism of action, and to uncover the molecular basis of why HMG-1/-2 in steroid receptor function receptors only.
The specific aims of this proposal include the following.
AIM #1 will determine the mechanism of HMG-1/-2 play essential roles in the function of a broad number of nuclear receptors by determining their influence on receptor-mediated transcription in HMG-1 genetically deficient mammalian and yeast cells.
AIM #3 will seek to uncover the molecular basis for why HMG-1/-2 influences only the steroid receptors and not the class II nuclear receptor. The hypothesis to be tested is that HMG-1/-2 interaction with the steroid receptor-DNA complex functionally substitutes for the minor groove-DNA interacting C-terminal extension (CTE) of the DNA binding domain (DBD) of other nuclear receptor.
AIM #4 will test the hypothesis that HMG-1/-2 plays a role in steroid receptor- mediated transcriptional activation by altering DNA binding site specificity and allowing receptors to function on weak affinity non- canonical hormone response elements. The expectation of this research is to establish whether HMG-1/-2 play an essential role in steroid receptor function and to uncover fundamental mechanistic differences in the way that steroid receptors and other classes of nuclear receptors interact with target genes.
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