tretinoin and Goiter

The tau4 domain in the extreme carboxyl (C) terminal region of thyroid hormone receptor (TR) is important to transactivation. We identified three truncated TRbeta1s with 11 (F451X), 13 (E449X) and 16 (C446X) amino acid deletions within this domain in subjects with resistance to thyroid hormone (RTH). F451X and C446X were found in a 6-year-old Japanese girl and a 31-year-old American male, respectively, who had both severe mental retardation. E449X was identified in a 16-year-old Japanese boy with no remarkable clinical symptoms except for goiter. Transient expression study revealed that all three mutants had negligible T3 binding and transcriptional activities. Each mutant TRbeta1 exhibited not only very strong dominant negative activity against wild TRbeta1, but also marked silencing activity. Interestingly, the dominant negative activity and silencing activity were significantly stronger in F451X than in E449X and C446X (P < 0.05). Gel-shift experiments revealed no apparent differences in homodimer formations of wild-type or mutant TRbeta1 proteins and in heterodimer formations with retinoid X receptor (RXR). These observations indicate that the tau4 domain affects diverse TR functions, and that the region between 11 and 13 C-terminal amino acids influences ligand-independent TR functions, including dominant negative and silencing activities. The central nervous system involvement is not necessarily determined by the dominant negative potency of the mutant TRbeta1 and other environmental or genetic factors may influence the RTH manifestations.

Topics: Adolescent; Adult; Animals; Base Sequence; Child; COS Cells; Dimerization; DNA; DNA Probes; Drug Resistance; Female; Goiter; Humans; In Vitro Techniques; Intellectual Disability; Male; Receptors, Thyroid Hormone; Recombinant Proteins; Sequence Deletion; Thyroid Hormone Resistance Syndrome; Transcriptional Activation; Transfection; Tretinoin; Triiodothyronine

In order to clarify the effect of retinoids on thyroid cell growth and function, the presence of retinoic acid receptors (RARs) and the action of retinoic acid (RA) on DNA synthesis and on thyroid peroxidase (TPO) and thyroglobulin (TGB) mRNA expression were investigated in primary cultures of human thyroid follicular cells. A time and dose-dependent reduction in 3H-thymidine (3H-thy) incorporation was found in cells exposed for 48 h to all-trans-RA up to 1 microM. A cytotoxic effect was found only with the higher dose of 50 microM. The RA-induced decrease of 3H-thy incorporation was reflected by parallel change in DNA content of cell monolayers. The inhibitory effect of 1 microM RA on 3H-thy incorporation ranged from 28.5 +/- 4.6% in normal cells to 42 +/- 3.2% in adenomatous cells. In addition, 1 microM RA significantly reduced basal and TSH-induced TPO mRNA levels in normal, goitrous and adenomatous cells, but did not alter TGB mRNA levels. Furthermore, in these cells the study of RAR alpha and beta mRNA showed the presence of two major RAR alpha mRNA transcripts of approximately 3.5 and 2.8 Kb in size, whereas RAR beta mRNA was undetectable. Overall, our data indicate that RAR alpha gene is expressed in human thyrocytes and that RA may be involved in the regulation of the human thyroid by reducing proliferation and function of follicular cells.

Topics: Adenoma; Carrier Proteins; Cells, Cultured; DNA; Gene Expression; Goiter; Humans; Iodide Peroxidase; Receptors, Retinoic Acid; RNA, Messenger; Thyroglobulin; Thyroid Gland; Thyroid Neoplasms; Tretinoin; Tumor Cells, Cultured