Mechanism of ATP-dependent transport by MRP1 protein

MRP1 蛋白的 ATP 依赖性转运机制

• 批准号: 7409658
• 负责人: Xiu-Bao Chang
• 金额: $ 23.76万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2009-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7409658
• 关键词: 5' -adenylyl (beta,gamma-methylene)diphosphonate; ABCC1 gene; ATP Hydrolysis; ATP phosphohydrolase; ATP-Binding Cassette Transporters; Acidic Amino Acids; Acute leukemia; Adenylyl Imidodiphosphate; Adult Non-Hodgkin' s Lymphoma; Affinity; Antineoplastic Agents; Apoptosis; Asparagine; Back; Binding; Breast; Cell membrane; Cells; Charge; Cysteine; Dissociation; Drug resistance; Glutamine; Glutathione; Hydrolysis; Inhibitory Concentration 50; Leukotriene C4; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Molecular Conformation; Multi-Drug Resistance; Multidrug Resistance Associated Protein 1; Multidrug Resistance-Associated Proteins; Mutate; Nucleotides; P-Glycoprotein; P-Glycoproteins; Pharmaceutical Preparations; Proteins; Rate; Research Personnel; Resistance; Set protein; Site; Solutions; Testing; Time; Vanadates; analog; base; cancer cell; cancer therapy; chemotherapy; inorganic phosphate; insight; malignant breast neoplasm; mutant; novel; programs; research study; solute; success

DESCRIPTION (provided by applicant): Chemotherapy remains the principal mode of cancer treatment. Unfortunately, the "intrinsic" and "acquired" multidrug resistance (MDR) of cancer cells limits the success of chemotherapeutic treatment of cancers. "Acquired" MDR indicates the fact that some cancers, such as breast, ovarian cancer, non-Hodgkin's lymphoma, adult acute leukemias and numerous childhood cancers, initially respond well to the chemotherapeutic treatment, but eventually become MDR during the treatment, reflecting different mechanisms from that of the "intrinsic" MDR. Over-expression of P-glycoprotein, breast cancer resistant protein and/or multidrug resistance-associated protein (MRP1) confers "acquired" MDR. Although all these ATP binding cassette (ABC) transporters transport anticancer drugs in an ATP dependent manner, different underlying mechanisms are involved. In addition, over-expression of these ABC transporters may not be the only reason to cause the "acquired" MDR. For example, over-expression of MRP1 decreases drug accumulation inside a cancer cell and results in MDR, whereas over-expression of Bcl-2 alters apoptosis pathways and results in decreased sensitivity to anticancer drugs. Thus, there might not be a simple solution to solve the "acquired" MDR caused by different mechanisms. A plausible strategy to reverse MDR is to understand the mechanism of each MDR, to treat each MDR individually and then to deal with MDR caused by multiple mechanisms globally. The objective proposed in this project is to elucidate the mechanism of ATP dependent solute transport by MRP1. Specific aims involved in this project are: 1. To test our hypothesis that ATP hydrolysis at NBD1 may not be essential for the ATP-dependent solute transport by MRP1; 2. To test whether or not the conformational changes induced by nucleotide binding at NBD1 and NBD2 are sufficient to transport the solute across the plasma membrane; 3. To test our hypothesis that nucleotide release from both NBDs facilitates the MRP1 protein to start a new cycle of ATP-dependent solute transport; 4. To determine the relationship between Km (ATP), Vmax (LTC4) and the drug resistance. New insights gained from these aims may provide the basis for novel means of combating MDR associated with over-expression of MRP1.

描述（由申请人提供）：化学疗法仍然是癌症治疗的主要模式。不幸的是，癌细胞的“固有”和“获得”的多药耐药性（MDR）限制了癌症化学治疗的成功。 MDR“获得”表明，某些癌症，例如乳腺癌，卵巢癌，非霍奇金淋巴瘤，成人急性白血病和许多儿童癌症，最初对化学治疗治疗的反应良好，但最终在治疗过程中成为MDR，反映了“内在” MDR的不同机制。 P-糖蛋白，抗乳腺癌蛋白和/或多药相关蛋白（MRP1）的过度表达“获得” MDR。尽管所有这些ATP结合盒（ABC）转运蛋白以ATP依赖性方式转运抗癌药，但涉及不同的潜在机制。另外，这些ABC转运蛋白的过表达可能不是引起“获得” MDR的唯一原因。例如，MRP1的过表达降低了癌细胞内的药物积累并导致MDR，而Bcl-2的过表达会改变凋亡途径，并导致对抗癌药物的敏感性降低。因此，可能没有一个简单的解决方案来解决由不同机制引起的“获得” MDR。逆转MDR的合理策略是了解每个MDR的机制，以单独处理每个MDR，然后处理由全球多种机制引起的MDR。该项目提出的目标是阐明MRP1依赖ATP溶质转运的机理。该项目涉及的具体目的是：1。检验我们的假设，即NBD1的ATP水解对于MRP1的ATP依赖性溶质转运可能不是必不可少的。 2。为了测试NBD1和NBD2处核苷酸结合引起的构象变化是否足以将溶质跨越质膜； 3。为了测试我们的假设，即从两个NBD中释放核苷酸促进了MRP1蛋白，以开始新的ATP依赖性溶质转运循环。 4。确定KM（ATP），VMAX（LTC4）与耐药性之间的关系。从这些目标中获得的新见解可能为与MRP1过表达相关的新型MDR打击提供基础。

项目成果

Interaction between the bound Mg.ATP and the Walker A serine residue in NBD2 of multidrug resistance-associated protein MRP1 plays a crucial role for the ATP-dependent leukotriene C4 transport.

结合的 Mg.ATP 与多药耐药相关蛋白 MRP1 的 NBD2 中的 Walker A 丝氨酸残基之间的相互作用对于 ATP 依赖性白三烯 C4 转运起着至关重要的作用。

• DOI: 10.1021/bi8007643
• 发表时间: 2008
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Yang,Runying;Scavetta,Robert;Chang,Xiu-bao
• 通讯作者: Chang,Xiu-bao

ATP binding to the first nucleotide binding domain of multidrug resistance-associated protein plays a regulatory role at low nucleotide concentration, whereas ATP hydrolysis at the second plays a dominant role in ATP-dependent leukotriene C4 transport.

与多药耐药相关蛋白的第一个核苷酸结合域结合的 ATP 在低核苷酸浓度下发挥调节作用，而第二个核苷酸结合域的 ATP 水解在 ATP 依赖性白三烯 C4 转运中起主导作用。

• DOI: 10.1074/jbc.m304118200
• 发表时间: 2003
• 期刊: The Journal of biological chemistry
• 作者: Yang,Runying;Cui,Liying;Hou,Yue-xian;Riordan,JohnR;Chang,Xiu-bao
• 通讯作者: Chang,Xiu-bao

Human Breast Cancer Stem Cells Have Significantly Higher Rate of Clathrin-Independent and Caveolin-Independent Endocytosis than the Differentiated Breast Cancer Cells.

• DOI: 10.4172/1948-5956.1000144
• 发表时间: 2012-07
• 期刊: Journal of cancer science & therapy
• 作者: Kanagaraj Palaniyandi;B. Pockaj;S. Gendler;X. Chang

Hydrogen-bond formation of the residue in H-loop of the nucleotide binding domain 2 with the ATP in this site and/or other residues of multidrug resistance protein MRP1 plays a crucial role during ATP-dependent solute transport.

• DOI: 10.1016/j.bbamem.2006.11.009
• 发表时间: 2007-02
• 期刊: Biochimica et biophysica acta
• 作者: Runying Yang;X. Chang

Verapamil and its derivative trigger apoptosis through glutathione extrusion by multidrug resistance protein MRP1.

Verapamil 及其衍生物通过多药耐药蛋白 MRP1 排出谷胱甘肽来触发细胞凋亡。

• DOI: 10.1158/0008-5472.can-04-0143
• 发表时间: 2004
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Trompier,Doriane;Chang,Xiu-Bao;Barattin,Régis;duMoulinetD'Hardemare,Amaury;DiPietro,Attilio;Baubichon-Cortay,Hélène
• 通讯作者: Baubichon-Cortay,Hélène