REGULATORY EFFECTS OF HEME TRANSPORT INTO LIVER CELLS

描述：血凝素是一种血浆糖蛋白，可将血红素输送到肝脏 细胞通过一个特定的受体介导的过程。血红素加氧酶，a 微粒体膜酶，催化起始和限速步骤 亚铁血红素降解。从血红素中释放出来的铁分子沉积在 铁蛋白簇。这些蛋白质的协同作用使得 保护对生物有用的铁，防止有毒物质的积累 血红素分子和抑制入侵微生物的生长。这个 我们研究的长期目标是更好地了解 血红素和铁的代谢，特别强调血凝素的作用 和血红素加氧酶在逆境下维持血红素和铁的动态平衡 条件(例如，由于遗传性疾病引起的血管内溶血 和/或由以下原因引起的细菌或病毒感染或细胞应激 环境毒素)。这项研究计划的一个方面是 血红素加氧酶基因作用机制的生化表征 底物血红素和应激相关物质的激活反应。 血红素对血红素加氧酶的调节是目前提案的重点。 这项提案的具体目标，代表了 自上次竞争以来在过去三年中进行的研究 综述：1)定义最小的血红素反应元素(HRE)： 突变分析：功能和蛋白质结合研究。2)隔离 并鉴定了HRE结合蛋白(HRE-Bps)及其相应的 CDNA克隆。3)确定哪个HRE-bps通过以下方式调节血红素反应性 抑制特定的HRE-BP表达(即，鉴定 血红素反应因子)。 血红素和其他血红素加氧酶诱导剂的一个共同特征是 它们会产生细胞内的氧化应激。由于促氧化剂(或 氧化状态)与过多的人类病理有关 包括动脉粥样硬化、缺血/复氧、损伤和癌症， 目前的研究结果应该会加深我们对 这些疾病的生物学。

DESCRIPTION: Hemopexin, a plasma glycoprotein, transports heme into liver cells by a specific, receptor-mediated process. Heme oxygenase, a microsomal membrane enzyme, catalyzes the initial and rate-limiting step in heme degradation. The iron molecule released from heme is deposited on ferritin clusters. The concerted action of these proteins permits conservation of biologically useful iron, prevents accumulation of toxic heme molecules and inhibits the growth of invading microorganisms. The long-term objective of our research is to better understand the processes of heme and iron metabolism, with particular emphasis on the role of hemopexin and heme oxygenase in maintaining heme and iron homeostasis under adverse conditions (e.g., during intravascular hemolysis due to hereditary disorders and/or bacterial or viral infections or cellular stress caused by environmental toxins). One aspect of this research program is the biochemical characterization of the mechanism of heme oxygenase gene activation in response to the substrate heme and stress-associated agents. Regulation of heme oxygenase by heme is the focus of the current proposal. The specific aims of this proposal, which represents a logical extension of the studies carried out in the past three years since the last competitive review, are 1) to define the minimal heme-responsive element (HRE) by mutational analysis: functional and protein binding studies. 2) to isolate and characterize the HRE binding proteins (HRE-BPs) and their corresponding cDNA clones. 3) to determine which HRE-BPs mediate heme responsiveness by inhibition of specific HRE-BP expression (i.e., identification of the heme-response factor). A common feature among heme and other inducers of heme oxygenase is that they generate intracellular oxidative stress. Since pro-oxidants (or oxidative states) have been implicated in a plethora of human pathologies including atherosclerosis, ischemia/reoxy-genation, injury, and cancer, the results from the present studies should further our knowledge of the basic biology of these diseases.