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Volume 271, Number 39, Issue of September 27, 1996 pp. 24213-24220
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Thyroid Hormone Receptor 2 Promoter Activity in Pituitary Cells Is Regulated by Pit-1

(Received for publication, January 17, 1996, and in revised form, July 1, 1996)

From the Division of Endocrinology, University of Colorado Health Sciences Center, Denver, Colorado 80262

There are three known thyroid hormone receptor (TR) isoforms that arise from two distinct  and  gene loci. TR1 and TR1 mRNAs are found in many tissues, whereas mRNA for the N-terminal TR2 variant derived from the  locus is readily detectable only in the pituitary gland and derived cell sources such as GH3 somatotropes and TtT-97 thyrotropes. We previously isolated the genomic region governing expression of the TR2 isoform in thyrotropes and showed that transcription arose from multiple origins within a 400-base pair (bp) region. We now report that the region extending 500 bp upstream of the putative AUG codon (A is +1) contains six areas of interaction with the pituitary-specific transcription factor Pit-1. In addition there are separate areas that bind other factors present in thyrotrope cells. Promoter deletions revealed that removal of regions containing the Pit-1 sites at 456 to 432, 149 to 127, and 124 to 102 progressively decreased TR2 promoter activity in thyrotropes. A more proximal footprinted area from 65 to 19, which accounted for the remaining promoter activity, contained sites that interacted with recombinant Pit-1; however, extracts of TtT-97 thyrotropes, which express Pit-1, footprinted this proximal region with a pattern of protection that differed from that produced by Pit-1. A comparative deletional analysis demonstrated that a shorter region extending only 204 bp from the AUG was sufficient to support TR2 promoter activity in GH3 somatotropes. The more proximal Pit-1 sites, including the area from 53 to 19, whose pattern differed from Pit-1 in thyrotrope extracts, showed protection patterns with GH3 extracts that were indistinguishable from recombinant Pit-1. Site-directed mutagenesis that abrogated binding of both recombinant Pit-1 and Pit-1-containing nuclear extracts revealed that the two Pit-1 sites between 149 and 102 were important for TR2 promoter activity with the more proximal being most critical. Finally, we showed that TR2 promoter activity in -TSH cells, which do not transcribe the endogenous TR2 locus or produce Pit-1 protein, could be reconstituted to a level approaching that seen in expressing TtT-97 thyrotropes by cotransfecting a Pit-1 expression vector. Activation by Pit-1 was dependent on the same Pit-1 sites shown to be important for basal TR2 promoter activity in thyrotropes as constructs lacking them by deletion or mutation were not stimulated by Pit-1.

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