Thyroid hormone (T3) is critical for normal human growth and development, as well as for healthy adult life. Regulation of gene transcription in diverse tissues is mediated by nuclear T3 receptors (TRs). TRs are cellular homologues of the erbA oncogene product, structurally similar to receptors for steroid hormones, vitamin D. and retinoic acid. Complementary DNAs encoding multiple TRs (alpha 1, beta 1, and beta 2) as well as a non-T3-binding variant (c-erbAalpha2) have been isolated and characterized. The mRNA corresponding to each is expressed in a tissue-specific pattern. The TRs must bind T3 as well as T3-responsive elements (TREs) in target genes to activate transcription. cerbAalpha2 is able to inhibit this process. This laboratory is interested in the expression, structure, and function of TRs and c-erbAalpha2.
The specific aims of this proposal are to: (1) study the regulation of TR expression, (2) compare and contrast the TRE-binding properties of endogenous and recombinant TRs. (3) identify and characterize nuclear proteins which interact with TRs, and (4) determine the regions of the TRs responsible for interaction with one another and with other nuclear proteins. Regulation of TR gene expression by sodium butyrate, cholera toxin, and retinoic acid will be investigated. Antibodies will be raised against peptides corresponding to specific regions of the TRs, and used to confirm and quantitate endogenous TR expression. TRs will be expressed in reticulocyte lysates and in yeast, and compared with endogenous TRs in gel electrophoretic mobility shift and footprint analyses using TRE-containing DNA fragments. Nuclear proteins which interact with TRs will be characterized in gel mobility shift assays, purified, and identified. Deletion and site-directed mutagenesis of the TRs will be employed to dissect out the regions of the TRs involved in these interactions, and in TR oligomerization. The long term goals of this work are to delineate the mechanisms by which TRs influence transcription, and to clarify the specific functions of the multiple TRs. This knowledge will not only be of tremendous value for our understanding of the role of TRs in health and disease, but should greatly impact on our general conceptualization of mechanisms of hormone action.
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