Department of Anatomy and Neurobiology, University of California-Irvine, Irvine, CA 92697, USA.
Department of Pediatrics, University of California-Irvine, Irvine, CA 92697, USA.
Stress. 2014 Jan;17(1):39-50. doi: 10.3109/10253890.2013.806907. Epub 2013 Jul 5.
Corticotropin-releasing hormone (CRH) contributes crucially to the regulation of central and peripheral responses to stress. Because of the importance of a finely tuned stress system, CRH expression is tightly regulated in an organ- and brain region-specific manner. Thus, in the hypothalamus, CRH is constitutively expressed and this expression is further enhanced by stress; however, the underlying regulatory mechanisms are not fully understood. The regulatory region of the crh gene contains several elements, including the cyclic-AMP response element (CRE), and the role of the CRE interaction with the cyclic-AMP response element binding protein (CREB) in CRH expression has been a focus of intensive research. Notably, whereas thousands of genes contain a CRE, the functional regulation of gene expression by the CRE:CREB system is limited to ∼100 genes, and likely requires additional proteins. Here, we investigated the role of a member of the CREB complex, CREB binding protein (CBP), in basal and stress-induced CRH expression during development and in the adult. Using mice with a deficient CREB-binding site on CBP, we found that CBP:CREB interaction is necessary for normal basal CRH expression at the mRNA and protein level in the nine-day-old mouse, prior to onset of functional regulation of hypothalamic CRH expression by glucocorticoids. This interaction, which functions directly on crh or indirectly via regulation of other genes, was no longer required for maintenance of basal CRH expression levels in the adult. However, CBP:CREB binding contributed to stress-induced CRH expression in the adult, enabling rapid CRH synthesis in hypothalamus. CBP:CREB binding deficiency did not disrupt basal corticosterone plasma levels or acute stress-evoked corticosterone release. Because dysregulation of CRH expression occurs in stress-related disorders including depression, a full understanding of the complex regulation of this gene is important in both health and disease.
促肾上腺皮质激素释放激素（CRH）对中枢和外周对应激的反应调节起着至关重要的作用。由于应激系统的精细调节非常重要，因此 CRH 的表达在器官和脑区特异性的方式下受到严格调节。因此，在下丘脑中，CRH 持续表达，这种表达进一步被应激增强；然而，其潜在的调节机制尚未完全理解。CRH 基因的调节区包含几个元件，包括环磷酸腺苷反应元件（CRE），并且 CRE 与环磷酸腺苷反应元件结合蛋白（CREB）的相互作用在 CRH 表达中的作用一直是密集研究的焦点。值得注意的是，虽然数千个基因包含 CRE，但 CRE：CREB 系统对基因表达的功能调节仅限于约 100 个基因，并且可能需要其他蛋白质。在这里，我们研究了 CREB 复合物的成员 CREB 结合蛋白（CBP）在发育过程中和成年期对基础和应激诱导的 CRH 表达的作用。使用 CBP 上 CREB 结合位点缺失的小鼠，我们发现 CBP：CREB 相互作用对于 9 天大的小鼠下丘脑 CRH 表达的功能调节之前的基础 CRH 表达的 mRNA 和蛋白水平是必需的。这种相互作用，其直接作用于 crh 或间接通过调节其他基因，对于成年期基础 CRH 表达水平的维持不再是必需的。然而，CBP：CREB 结合有助于成年期应激诱导的 CRH 表达，使下丘脑的 CRH 合成迅速。CBP：CREB 结合缺陷不会破坏基础皮质酮血浆水平或急性应激诱导的皮质酮释放。由于 CRH 表达的失调发生在包括抑郁症在内的应激相关疾病中，因此对该基因的复杂调节的全面理解在健康和疾病中都很重要。
