Drouin J, Charron J, Gagner J P, Jeannotte L, Nemer M, Plante R K, Wrange O
Laboratoire de Biologie Moléculaire des Eucaryotes, Institut de Recherches Cliniques de Montréal, Canada.
J Cell Biochem. 1987 Dec;35(4):293-304. doi: 10.1002/jcb.240350404.
The gene encoding pro-opiomelanocortin (POMC) offers an interesting model system to study negative control of transcription in eucaryotes. Indeed, glucocorticoid hormones specifically inhibit transcription of the POMC gene in the anterior pituitary. The POMC gene is predominantly expressed in the anterior and intermediate lobes of the pituitary. However, only anterior pituitary POMC transcription is inhibited by glucocorticoids and stimulated by corticotropin-releasing hormone (CRH). Rat POMC promoter sequences required for anterior pituitary-specific expression were localized between positions -480 and -34 base pairs (bp) by DNA-mediated gene transfer into the POMC-expressing tumor cells. AtT-20. These POMC promoter sequences also confer glucocorticoid inhibition of transcription. While two of the six in vitro binding sites for purified glucocorticoid receptor identified in the rat POMC gene are within these sequences, only one is required for glucocorticoid inhibition; this binding site is located at position -63 bp in the promoter and overlaps a putative CCAAT box sequence. The DNA sequence of the POMC -63 bp receptor binding site is homologous to receptor binding sites identified in the glucocorticoid responsive element (GRE) of glucocorticoid-inducible genes. However, DNA sequence divergencies between these sites, in particular within the conserved hexanucleotide sequence 5'-TGTYCT-3', may be involved in their opposite transcriptional activity. Alternatively, binding of the receptor in the promoter proximal region of the POMC gene may inhibit transcription by a hormone-dependent repressor mechanism.
编码阿黑皮素原（POMC）的基因提供了一个有趣的模型系统，用于研究真核生物中转录的负调控。实际上，糖皮质激素特异性抑制垂体前叶中POMC基因的转录。POMC基因主要在垂体的前叶和中间叶表达。然而，只有垂体前叶的POMC转录受到糖皮质激素的抑制，并受到促肾上腺皮质激素释放激素（CRH）的刺激。通过DNA介导的基因转移到表达POMC的肿瘤细胞AtT-20中，确定了垂体前叶特异性表达所需的大鼠POMC启动子序列位于-480至-34碱基对（bp）之间。这些POMC启动子序列也赋予糖皮质激素对转录的抑制作用。虽然在大鼠POMC基因中鉴定出的六个纯化糖皮质激素受体的体外结合位点中有两个在这些序列内，但糖皮质激素抑制只需要其中一个；这个结合位点位于启动子的-63 bp位置，与一个假定的CCAAT框序列重叠。POMC -63 bp受体结合位点与糖皮质激素诱导基因的糖皮质激素反应元件（GRE）中鉴定出的受体结合位点具有同源性。然而，这些位点之间的DNA序列差异，特别是在保守的六核苷酸序列5'-TGTYCT-3'内，可能与它们相反的转录活性有关。或者，受体在POMC基因启动子近端区域的结合可能通过激素依赖性阻遏机制抑制转录。
