This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lin, K.-h. Articles by Cheng, S.-y. Search for Related Content PubMed PubMed Citation Articles by Lin, K.-h. Articles by Cheng, S.-y.

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.

This article has been cited by other articles:

				M. D. Rosen and M. L. Privalsky Thyroid Hormone Receptor Mutations Found in Renal Clear Cell Carcinomas Alter Corepressor Release and Reveal Helix 12 as Key Determinant of Corepressor Specificity Mol. Endocrinol., August 1, 2009; 23(8): 1183 - 1192. [Abstract] [Full Text] [PDF]

				O. Martinez-Iglesias, S. Garcia-Silva, S. P. Tenbaum, J. Regadera, F. Larcher, J. M. Paramio, B. Vennstrom, and A. Aranda Thyroid Hormone Receptor {beta}1 Acts as a Potent Suppressor of Tumor Invasiveness and Metastasis Cancer Res., January 15, 2009; 69(2): 501 - 509. [Abstract] [Full Text] [PDF]

				A. S. Rocha, R. Marques, I. Bento, R. Soares, J. Magalhaes, I. V. de Castro, and P. Soares Thyroid hormone receptor {beta} mutations in the 'hot-spot region' are rare events in thyroid carcinomas J. Endocrinol., January 1, 2007; 192(1): 83 - 86. [Abstract] [Full Text] [PDF]

				K.-H. Lin, W.-J. Wang, Y.-H. Wu, and S.-Y. Cheng Activation of Antimetastatic Nm23-H1 Gene Expression by Estrogen and Its {alpha}-Receptor Endocrinology, February 1, 2002; 143(2): 467 - 475. [Abstract] [Full Text] [PDF]

				Y. Kamiya, M. Puzianowska-Kuznicka, P. McPhie, J. Nauman, S.-y. Cheng, and A. Nauman Expression of mutant thyroid hormone nuclear receptors is associated with human renal clear cell carcinoma Carcinogenesis, January 1, 2002; 23(1): 25 - 33. [Abstract] [Full Text] [PDF]

				L. D. Miller, K. S. Park, Q. M. Guo, N. W. Alkharouf, R. L. Malek, N. H. Lee, E. T. Liu, and S.-y. Cheng Silencing of Wnt Signaling and Activation of Multiple Metabolic Pathways in Response to Thyroid Hormone-Stimulated Cell Proliferation Mol. Cell. Biol., October 1, 2001; 21(19): 6626 - 6639. [Abstract] [Full Text] [PDF]

				K.-h. Lin and Y.-h. Wu shen-liang chen Impaired Interaction of Mutant Thyroid Hormone Receptors Associated with Human Hepatocellular Carcinoma with Transcriptional Coregulators Endocrinology, February 1, 2001; 142(2): 653 - 662. [Abstract] [Full Text] [PDF]

				K.-h. Lin, H.-y. Shieh, and H.-C. Hsu Negative Regulation of the Antimetastatic Gene Nm23-H1 by Thyroid Hormone Receptors Endocrinology, July 1, 2000; 141(7): 2540 - 2547. [Abstract] [Full Text] [PDF]