Regulation of heme oxygenase-1 by biliverdin reductase

胆绿素还原酶对血红素加氧酶 1 的调节

• 批准号: 8106400
• 负责人: Mahin D. Maines
• 金额: $ 33.2万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8106400
• 关键词: Address; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antioxidants; Apoptotic; Beryllium; Bilirubin; Biliverdin reductase; Biliverdine; Binding; Binding Sites; Biological; Blood Circulation; CREB1 gene; Catalysis; Cell Differentiation process; Cell Line; Cell Nucleus; Cell physiology; Cells; Chemicals; Co-Immunoprecipitations; Complex; Containment; Creatinine; Cultured Cells; Cyclic AMP; Cytoplasm; Cytoprotection; Cytosol; DNA; DNA Binding; Data; Defense Mechanisms; Dimerization; Disease; Docking; Dominant-Negative Mutation; Doxycycline; Elements; Enhancers; Enzymes; Erythrocytes; Event; Exposure to; FOS gene; Family; Family member; Free Radicals; Functional disorder; Funding; Gel; Gelshift Analysis; Gene Expression; Genes; Genetic Transcription; Growth Factor Receptors; Half-Life; Health; Heme; Hemeproteins; Hemoglobin; Hemolysis; Homo; Human; In Vitro; Individual; Inflammation; Inherited; Injury; Insulin Receptor; Investigation; Iron; Isomerism; JUN gene; Kidney; Kidney Failure; Link; Liver; MAP Kinase Gene; Mediating; Mediator of activation protein; Membrane; Molecular; Monitor; Morphology; Mus; Nuclear; Nuclear Translocation; One-Step dentin bonding system; Operative Surgical Procedures; Organ; Organ Transplantation; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; Oxygenases; Pathway interactions; Pharmaceutical Preparations; Phenylhydrazines; Phosphopeptides; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiology; Plasmids; Process; Protein Binding; Protein Kinase; Protein-Serine-Threonine Kinases; Proteins; Rattus; Reactive Oxygen Species; Regulation; Regulatory Element; Renal carcinoma; Renal function; Renal tubule structure; Reperfusion Injury; Research; Response Elements; Role; Series; Serine; Serum; Signal Pathway; Signal Transduction; Site; Site-Directed Mutagenesis; Small Interfering RNA; Source; Specificity; Stimulus; Stress; Structure; Testing; Tetrapyrroles; Threonine; Tissues; Toxic effect; Toxicology; Transcription Factor AP-1; Transgenic Mice; Translating; Tyrosine; Vasodilation; Yeasts; activating transcription factor; angiogenesis; bZIP Domain; base; biological adaptation to stress; catalyst; dimer; environmental agent; free radical oxygen; heme oxygenase-1; heme oxygenase-2; human CREB3 protein; in vivo; inhibitor/antagonist; insight; kidney cell; member; mouse model; novel therapeutic intervention; nucleocytoplasmic transport; oxidation; phenylhydrazine; promoter; protein degradation; protein protein interaction; protoporphyrin IX; research study; response; trafficking; transcription factor; transgene expression; yeast two hybrid system

DESCRIPTION (provided by applicant): The heme moiety of denatured hemoproteins (heme-proteins) is degraded by HO-1 & HO-2, to CO and biliverdin (BV), an HO activity inhibitor; BV is reduced by its reductase (BVR) to the antioxidant, bilirubin. CO has anti-inflammatory and vasodilatory activities. Stimuli that cause oxidative stress and hemoprotein denaturation, such as surgical interventions, inherited and transmitted hemolytic diseases, and certain drugs, industrial and environmental agents, induce ho-1. The kidney tubules are the target of potent pro-oxidant activity of heme-compounds. To date, no effective strategy has been described to counter heme-protein renal toxicity; however, increase in HO-1 activity by activation of stress-activated response elements, e.g., AP-1/CRE, AREs (antioxidant response elements) is considered cytoprotective. The activation involves cell-line independent binding of basic leucine zipper (bZip) transcription factors: c-Jun, ATF- 2/CREB, and Nrf2. The MAPK and PI3-K pathways transduce signals for activation of bZip factors and "cross talk" using PKCs. bZip factor activity is subject to the identity of its dimeric partner. Phosphorylation of the ultimate target gene product, e.g., HO-1, alters its activity and turnover. In vitro and in cultured cells, we have discovered that: the human (h) BVR is one of the rare kinases that control MAPK and PI3-K signaling; is a bZip factor; activated by ho-1 inducers; and, traffics between the cytosol and nucleus. hBVR binds to AP-l/CRE and ARE elements and also enhances ATF-2 and Nrf2 binding to AP-1 and/or ARE; promotes induction and activation of ATF-2, c-Jun and c-Fos; activates kinase mediators of ho-1 response, i.e. PKCs and PKB/Akt; and, causes cell differentiation. BVR regulates ho-1 oxidative stress response and its anti-apoptotic effect. The overall objective of this application is to further investigate regulation of HO-1 activity by BVR at the molecular and cellular levels and to extend the investigation to the intact animal. Specific aims are to examine: i) function of BVR as kinase:kinase in phosphorylation, activity, and turnover of HO-1; 2) the role of hBVR in transcriptional activity of ATF-2 and Nrf2; and, 3) whether increased levels of BVR protect against heme-mediated injury. Mice expressing hBVR in renal tubules and treated with the hemolytic agent, phenylhydrazine, will be analyzed for pathophysiology, antioxidant status, kinase activities and HO-1 levels. Liver will serve as the non-target organ as control for the expression of the transgene.

描述（申请人提供）：变性血红素蛋白（血红素蛋白）的血红素部分被 HO-1 和 HO-2 降解为 CO 和胆绿素 (BV)（一种 HO 活性抑制剂）； BV 被其还原酶 (BVR) 还原为抗氧化剂胆红素。 CO 具有抗炎和血管舒张活性。引起氧化应激和血红素蛋白变性的刺激，例如手术干预、遗传性和传播性溶血性疾病以及某些药物、工业和环境因素，都会诱导 ho-1。肾小管是血红素化合物有效促氧化活性的目标。迄今为止，还没有有效的策略来对抗血红素蛋白的肾毒性。然而，通过激活应激激活反应元件（例如 AP-1/CRE、ARE（抗氧化反应元件））来增加 HO-1 活性被认为具有细胞保护作用。该激活涉及细胞系独立的碱性亮氨酸拉链 (bZip) 转录因子的结合：c-Jun、ATF-2/CREB ​​和 Nrf2。 MAPK 和 PI3-K 通路转导信号以激活 bZip 因子并使用 PKC 进行“串扰”。 bZip 因子活性取决于其二聚体伙伴的身份。最终靶基因产物（例如 HO-1）的磷酸化会改变其活性和周转率。在体外和培养细胞中，我们发现： 人类 (h) BVR 是控制 MAPK 和 PI3-K 信号传导的稀有激酶之一；是 bZip 因子；由ho-1诱导剂激活；并且，细胞质和细胞核之间的交通。 hBVR 结合 AP-1/CRE 和 ARE 元件，并且还增强 ATF-2 和 Nrf2 与 AP-1 和/或 ARE 的结合；促进 ATF-2、c-Jun 和 c-Fos 的诱导和激活；激活 ho-1 反应的激酶介质，即 PKC 和 PKB/Akt；并且，导致细胞分化。 BVR 调节 ho-1 氧化应激反应及其抗凋亡作用。本申请的总体目标是进一步研究 BVR 在分子和细胞水平上对 HO-1 活性的调节，并将研究扩展到完整的动物。具体目标是检查： i) BVR 作为激酶：HO-1 磷酸化、活性和更新中的激酶的功能； 2) hBVR在ATF-2和Nrf2转录活性中的作用； 3) BVR 水平的增加是否可以预防血红素介导的损伤。将分析肾小管中表达 hBVR 并接受溶血剂苯肼治疗的小鼠的病理生理学、抗氧化状态、激酶活性和 HO-1 水平。肝脏将作为非靶器官作为转基因表达的对照。