Mitsuhashi T, Uchimura H, Takaku F
J Biol Chem. 1987 Mar 25;262(9):3993-9.
The thyroid hormone nuclear receptor is a chromatin-associated protein regulating expression of specific genes. Acetylation of nucleosomal core histones is thought to be one of the factors regulating transcriptional activity of chromatin, and it is suggested that this reaction negatively regulates thyroid hormone receptor levels in GH1 cells (Samuels, H.H., Stanley, F., Casanova, J., and Shao, T. C. J. Biol. Chem. 255, 2499-2508). In the present study, we found that n-butyrate, a potent inhibitor of histone deacetylase, increases thyroid hormone receptor levels in three distinct non-pituitary cells without changing binding affinity. This effect appeared within 30 min and reached a plateau (240% of control) after a 6-h treatment, before important cellular functions were affected. This effect was time-dependent, dose-dependent, reversible, and paralleled the changes in the electrophoretic mobilities of histones H3 and H4. n-Butyrate prolonged the receptor half-life, and this prolongation corresponded to the increase of receptor levels. Thyroid hormone did not reduce its own receptor levels or influence the effect of n-butyrate. Considering the difference between GH1 cells and non-pituitary cells in the regulation of thyroid hormone receptor levels, our observations, together with those of Samuels et al., suggest the possibility that the acetylation of chromatin-associated proteins has a physiological significance in the regulation of thyroid hormone nuclear receptor levels.
甲状腺激素核受体是一种与染色质相关的蛋白质，可调节特定基因的表达。核小体核心组蛋白的乙酰化被认为是调节染色质转录活性的因素之一，并且有人提出这种反应会负向调节GH1细胞中甲状腺激素受体的水平（塞缪尔斯，H.H.，斯坦利，F.，卡萨诺瓦，J.，以及邵，T.C.《生物化学杂志》255，2499 - 2508）。在本研究中，我们发现丁酸（一种组蛋白脱乙酰酶的强效抑制剂）可在三种不同的非垂体细胞中增加甲状腺激素受体水平，而不改变其结合亲和力。这种效应在30分钟内出现，经过6小时处理后达到平台期（为对照的240%），此时重要的细胞功能尚未受到影响。这种效应具有时间依赖性、剂量依赖性、可逆性，并且与组蛋白H3和H4的电泳迁移率变化平行。丁酸延长了受体的半衰期，这种延长与受体水平的增加相对应。甲状腺激素不会降低其自身受体水平，也不影响丁酸的作用。考虑到GH1细胞与非垂体细胞在甲状腺激素受体水平调节方面的差异，我们的观察结果与塞缪尔斯等人的结果共同表明，染色质相关蛋白的乙酰化在甲状腺激素核受体水平的调节中可能具有生理意义。
