Dynamic Regulation of Erythropoietin Gene Expression in Mammals

贫血是退伍军人患者的常见疾病，也是增加 伴随其他疾病状态时的发病率和死亡率。当前贫血的治疗方法 涉及非生理性推注促红细胞生成素(EPO)，这是一种产生于 成人严重贫血的肾脏和肝脏。推注促红细胞生成素管理有不良影响，包括 增加血栓形成的风险和对癌症的刺激作用。了解如何监管EPO 将允许研究人员开发除EPO替代外的合理疗法。 我们目前的重点是定义调控EPO表达的分子机制 哺乳动物。缺氧诱导因子(HIF)转录因子是由三个分子组成的家族 诱导细胞对低氧产生保护性反应的介质。第二个低氧诱导因子成员HIF-2α是 对体内EPO基因的表达至关重要。而缺氧诱导因子-2α在促红细胞生成素调节中的重要作用 公认的，导致体内瞬时EPO基因表达或异常的因素 贫血患者中EPO基因表达的抑制仍然知之甚少。 尽管HIF-2α经历了氧依赖的翻译后修饰，但这 机制并不是控制HIF-2信号的唯一机制，甚至不是主要机制。的活动 低氧诱导因子-1α是低氧诱导因子的创始成员，主要受氧依赖的翻译后调控 HIF-1α蛋白的修饰，导致HIF-1α蛋白水平的显著变化。然而， 这一机制并不是调节HIF-2信号的唯一机制，甚至不是主要机制。 相反，缺氧诱导因子-2的α活性受两种相反的和翻译后修饰--乙酰化的控制 以及去乙酰化，它们以循环的方式运行。 我们的中心假设是低氧触发中间代谢的变化，以 对缺氧诱导因子-2α乙酰化的影响。控制缺氧诱导因子-2α乙酰化的生化基础是通过一个实体 被称为醋酸盐开关，它将中间代谢的变化与乙酰辅酶A结合起来 一代。醋酸酯开关的分子介体是乙酰辅酶A合成酶2(Acss2)，一种 醋酸酯依赖的酶，产生特定的乙酰辅酶A池，用于诱导偶联 缺氧诱导因子-2α的乙酰化和活化。由于Acss2的一个子集在低氧期间转移到细胞核， Acss 2增强HIF-2α活性的能力可能是通过其定位于核来实现的 压力时的隔间。准确破译Acss2是如何调控HIF-2信号的 提供对正常促红细胞生成素调节的见解，确定潜在的病理生理机制 负责治疗贫血，并推动针对贫血患者的新疗法的开发。

Anemia, a common condition in Veteran patients, is a potent risk factor for increased morbidity and mortality when accompanying other disease states. Current therapies for anemia involve non-physiological bolus administration of erythropoietin (Epo), an endocrine factor produced in the adult kidney and liver with severe anemia. Bolus Epo administration has untoward effects, including an increased thrombotic risk and a stimulatory effect on cancer. Understanding how Epo is regulated will allow investigators to develop rational therapies besides Epo replacement. Our current focus is defining molecular mechanisms regulating Epo expression in mammals. Hypoxia Inducible Factor (HIF) transcription factors are a family of three molecular mediators that induce a protective cellular response to hypoxia. The second HIF member, HIF-2α, is critical for in vivo Epo gene expression. While an essential role of HIF-2α in Epo regulation is now recognized, the factors responsible for temporal Epo gene expression in vivo, or for abnormal repression of Epo gene expression in anemia patients, remain poorly understood. Although HIF-2α undergoes oxygen-dependent post-translational modifications, this mechanism is not the sole or even major mechanism for controlling HIF-2 signaling. Activity of HIF-1α, the founding HIF member, is controlled predominantly by oxygen-dependent post-translational modifications of the HIF-1α protein, which result in marked changes in HIF-1α protein levels. However, this mechanism is not the sole or even predominant mechanism for regulation of HIF-2 signaling. Instead, HIF-2α activity is controlled by two opposing and post-translational modifications, acetylation and deacetylation, that operate in a cyclical manner. Our central hypothesis is that hypoxia triggers changes in intermediary metabolism to effect acetylation of HIF-2α. The biochemical basis for control of HIF-2α acetylation is via an entity termed the acetate switch, which couples changes in intermediary metabolism with acetyl CoA generation. The molecular mediator for the acetate switch is acetyl CoA synthetase 2 (Acss2), an acetate-dependent enzyme that generates a specific pool of acetyl CoA used to induce coupled acetylation and activation of HIF-2α. Because a subset of Acss2 transits to the nucleus during hypoxia, the ability of Acss2 to augment HIF-2α activity may be conferred by its localization to the nuclear compartment during stress. Deciphering precisely how Acss2 regulates HIF-2 signaling will provide insights into normal Epo regulation, identify potential pathophysiological mechanisms responsible for anemia, and stimulate development of novel treatments for anemia patients.