Dominant negative activity of mutant thyroid hormone receptors from patients with hepatocellular carcinoma

Kwang Huei Lin, Xu Guang Zhu, Hai Chu Hsu, Shen Liang Chen, Hsing Ying Shieh, Szu Tah Chen, Peter McPhie, Sheue Yann Cheng

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Complementary DNAs for two mutant thyroid hormone α1 receptors (TRα1) 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 TRα1 (w-TRα1), which bound these TREe with different homodimer/monomer ratios, binding of mutant L to the three TREe 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- TRα1. The binding of these two mutants to the three TREe as heterodimers with retinoid X receptors (RXRα and -β) 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 > DP4 > Lys, whereas no TRE dependency was observed for mutant L. The present study indicates that mutations of the TRα gene de occur in patients and that these novel TRα1 mutants provide a valuable tool to further understand the molecular basis of the dominant negative action of mutant TRs.

Original languageEnglish
Pages (from-to)5308-5315
Number of pages8
JournalEndocrinology
Volume138
Issue number12
DOIs
StatePublished - 1997

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