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Activation of the Thyroid-Stimulating Hormone ß-Subunit Gene by LIM Homeodomain Transcription Factor Lhx2

Departments of Biochemistry (K.K.K., S.B.S., K.E.K.) and Biology (M.R.) and Institute of Biotechnology (K.I.K.), Chungnam National University, Daejeon 305-764, Korea

Address all correspondence and requests for reprints to: Kyoon Eon Kim, Ph.D., Department of Biochemistry, Chungnam National University, Daejeon 305-764, Korea. E-mail: kyoonkim{at}cnu.ac.kr.

Although there is evidence that the LIM homeodomain transcription factor, Lhx2, can stimulate transcription of the glycoprotein hormone -subunit gene, the role of Lhx2 in regulating TSH ß-subunit has not been established. In the present studies, the ability of Lhx2 to regulate transcription of the TSH ß-subunit gene was examined. In the thyrotrope-derived TT1 cell line, Lhx2 expression was found to be induced by treatment with either TRH or cAMP, consistent with the possibility that Lhx2 may play a role in mediating the ability of this signaling pathway to stimulate TSH gene expression. Transient, forced overexpression of Lhx2 stimulated activity of a TSH ß-subunit reporter gene. Deletion studies provided evidence that the –177 to –79 region of the TSH ß-subunit promoter was necessary for stimulation of reporter gene activity by Lhx2. A gel mobility shift assay provided the evidence that Lhx2 can bind to this region of DNA. DNase I footprinting studies demonstrated that two distinct regions of the TSHß promoter, –118 to –108 and –86 to –68, are protected by Lhx2 from nuclease digestion. These regions contain repeats of the sequence, 5'-(G/T)CAAT(T/A)-3'. Mutation of this sequence, especially in the –86 to –68 region, substantially decreased Lhx2 responsiveness of the TSH ß-subunit reporter gene. In addition, a DNA fragment containing the –177 to –79 region of the TSHß promoter was found to confer Lhx2 responsiveness to a minimal promoter. These results provide multiple lines of evidence consistent with a role for Lhx2 in modulating expression of the TSH ß-subunit gene.