Chatterjee V K, Tata J R
Department of Medicine, University of Cambridge Clinical School, Addenbrooke's Hospital.
Cancer Surv. 1992;14:147-67.
That most major physiological actions of thyroid hormones could be mediated via hormonal regulation of gene expression has been known for more than 25 years. The localization of TR in the cell nucleus, first reported almost 20 years ago, confirmed this concept. But it is only since the cloning of the TR gene and its identification as the c-erbA oncogene, accomplished 6 years ago, that we have begun to understand the details of the interaction between the hormone and its receptor and between the receptor and its target gene. Perhaps the most significant concept to emerge from the molecular studies is that the TR belongs to the superfamily of nuclear receptors for steroid hormones and morphogens such as retinoids. It highlights the evolutionary conservation of a major network of cellular signalling and intracellular regulatory pathways and which has helped bring us closer to a unified concept of the action of many growth and developmental hormones. Several important questions to be solved in the future become obvious from this brief review of the role of thyroid hormone in regulating developmental processes. Among these is the explantation for the high degree of tissue specificity of hormonal regulation of gene expression. The discovery of differential expression of the two major TR genes and the generation of multiple isoforms of the receptor by alternate splicing go some way to answering this question, but this is clearly not the sole factor determining tissue specificity. It will be most important to find out more about the interaction between the receptor and other transcription factors or nuclear proteins, some of which may be tissue specific and others expressed ubiquitously. The autoinduction of TR during amphibian metamorphosis, described above, emphasizes the intriguing question of how receptor genes are regulated during development. We know little as yet about the promoters and regulatory factors involved in this process. Finally, we have also described the recent recognition of genetic defects in TRs that underlie thyroid hormone linked diseases in humans. Future studies on the molecular genetics of receptors will enhance the importance in clinical practice of receptor linked diseases.
甲状腺激素的大多数主要生理作用可通过基因表达的激素调节来介导，这一认识已有25年多的时间。近20年前首次报道的甲状腺激素受体（TR）在细胞核中的定位证实了这一概念。但直到6年前完成TR基因的克隆并将其鉴定为c-erbA癌基因，我们才开始了解激素与其受体之间以及受体与其靶基因之间相互作用的细节。分子研究中出现的或许最重要的概念是，TR属于类固醇激素和类视黄醇等形态发生素的核受体超家族。它突显了细胞信号传导和细胞内调节途径主要网络的进化保守性，这有助于我们更接近许多生长和发育激素作用的统一概念。从对甲状腺激素在调节发育过程中作用的简要回顾中可以明显看出，未来有几个重要问题有待解决。其中之一是基因表达的激素调节具有高度组织特异性的原因。两种主要TR基因差异表达的发现以及通过可变剪接产生受体的多种异构体在一定程度上回答了这个问题，但这显然不是决定组织特异性的唯一因素。更深入了解受体与其他转录因子或核蛋白之间的相互作用将非常重要，其中一些可能是组织特异性的，另一些则普遍表达。上述两栖动物变态过程中TR的自诱导强调了发育过程中受体基因如何被调节这一有趣问题。我们对参与这一过程的启动子和调节因子了解甚少。最后，我们还描述了最近对人类甲状腺激素相关疾病所基于的TR基因缺陷的认识。未来对受体分子遗传学的研究将提高受体相关疾病在临床实践中的重要性。
