Dynamic Regulation of Erythropoietin Gene Expression in Mammals

贫血是退伍军人患者的一种常见疾病，是一个潜在的危险因素， 发病率和死亡率时，伴随其他疾病状态。贫血的当前疗法 包括促红细胞生成素（Epo）非生理性推注给药， 成人肾脏和肝脏严重贫血。大剂量Epo给药具有不良反应，包括 血栓形成风险增加和对癌症的刺激作用。了解Epo如何监管 将使研究人员开发出除了Epo替代之外的合理治疗方法。 我们目前的重点是确定调节Epo表达的分子机制， 哺乳动物缺氧诱导因子（Hypoxia Inducible Factor，HIF）是一个由三个分子组成的转录因子家族 介体，其诱导对缺氧的保护性细胞反应。第二个HIF成员HIF-2α， 对体内Epo基因表达至关重要。虽然HIF-2α在Epo调节中的重要作用现在被认为是 已经认识到，负责体内Epo基因瞬时表达或异常表达的因素， 贫血患者中Epo基因表达的抑制仍然知之甚少。 尽管HIF-2α经历氧依赖性翻译后修饰， 这一机制不是控制HIF-2信号传导的唯一甚至主要机制。活性 HIF-1α是HIF的创始成员，主要由氧依赖性的翻译后表达调控。 HIF-1α蛋白的修饰，这导致HIF-1α蛋白水平的显著变化。然而，在这方面， 该机制不是调节HIF-2信号传导的唯一或甚至主要机制。 相反，HIF-2α的活性是由两个相反的翻译后修饰控制的，乙酰化 和脱乙酰化，其以循环方式操作。 我们的中心假设是，缺氧引发中间代谢的变化， 影响HIF-2α乙酰化。控制HIF-2α乙酰化的生化基础是通过一个实体 称为乙酸开关，它将中间代谢的变化与乙酰辅酶A偶联 一代乙酸转换的分子介体是乙酰辅酶A合成酶2（Acss 2）， 一种乙酸依赖性酶，产生一种特异性的乙酰辅酶A库，用于诱导偶联 乙酰化和激活HIF-2α。因为Acss 2的一个子集在缺氧期间转移到细胞核， Acss 2增强HIF-2α活性的能力可能是由于其定位于细胞核， 压力下的车厢精确地破译Acss 2如何调节HIF-2信号传导将 提供正常Epo调节的见解，确定潜在的病理生理机制 负责贫血，并刺激开发新的治疗贫血患者。

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.