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Dominant Negative Activity of Mutant Thyroid Hormone 1 Receptors from Patients with Hepatocellular Carcinoma¹

Department of Biochemistry, Chang-Gung College of Medicine and Technology, Taoyuan, Taiwan; and Gene Regulation Section, Laboratory of Molecular Biology, National Cancer Institute and Laboratory of Biochemical Pharmacology (P.M.), National Institute of Diabetes and Digestive and Kidney Diseases (X.-G.Z., S.-y.C.), Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Kwang-huei Lin, Department of Biochemistry, Chang-Gung College of Medicine and Technology, Taoyuan, Taiwan.

Complementary DNAs for two mutant thyroid hormone 1 receptors (TR1) were isolated from hepatocellular carcinomas of two patients. Sequence analyses of the complementary DNAs showed a single Val³⁹⁰Ala and double Pro³⁹⁸Ser/Glu³⁵⁰Lys mutations in mutants H and L, respectively. We characterized their hormone-binding, DNA-binding, and dominant negative activities. Mutants H and L did not bind the hormone T₃. Their DNA-binding activities were analyzed using three types of thyroid hormone response elements (TREs) in which the half-site binding motifs are arranged in an everted repeat (Lys), an inverted repeat (Pal), or a direct repeat separated by four nucleotides (DR4). Compared with wild-type TR1 (w-TR1), which bound these TREs with different homodimer/monomer ratios, binding of mutant L to the three TREs as homodimers was reduced by 90%. However, binding of mutant H to these TREs was more complex. Although it bound normally to DR4 as homodimers, its binding to Lys as homodimers was reduced by 80%. Surprisingly, its binding to Pal was markedly enhanced compared with w-TR1. The binding of these two mutants to the three TREs as heterodimers with retinoid X receptors (RXR and -ß) was not significantly affected. Consistent with the lack of T₃-binding activity, both mutants had lost their trans-activation capacity. Mutants H and L exhibited dominant negative activity, but differed in their TRE dependency. The dominant negative potency of mutant H was in the rank order of Pal > DR4 > Lys, whereas no TRE dependency was observed for mutant L. The present study indicates that mutations of the TR gene do occur in patients and that these novel TR1 mutants provide a valuable tool to further understand the molecular basis of the dominant negative action of mutant TRs.

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