Mechanism of ATP-dependent transport by MRP1 protein

MRP1 蛋白的 ATP 依赖性转运机制

基本信息

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
项目类别：
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&apos -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&apos 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

项目摘要

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）：化疗仍然是癌症治疗的主要方式。不幸的是，癌细胞的“内在”和“获得性”多药耐药性（MDR）限制了癌症化疗的成功。 “获得性”MDR表明一些癌症，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，最初对化疗治疗反应良好，但最终在治疗过程中变成MDR，反映了不同的机制来自“内在”MDR。 P-糖蛋白、乳腺癌抗性蛋白和/或多药抗性相关蛋白（MRP1）的过度表达导致“获得性”MDR。尽管所有这些 ATP 结合盒 (ABC) 转运蛋白都以 ATP 依赖性方式转运抗癌药物，但涉及不同的潜在机制。此外，这些ABC转运蛋白的过度表达可能并不是导致“获得性”MDR的唯一原因。例如，MRP1 的过度表达会减少癌细胞内的药物积累并导致 MDR，而 Bcl-2 的过度表达会改变细胞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“获得性”MDR。逆转MDR的一个可行策略是了解每种MDR的机制，单独对待每种MDR，然后全局处理由多种机制引起的MDR。该项目提出的目标是阐明 MRP1 依赖 ATP 的溶质转运机制。该项目涉及的具体目标是： 1. 检验我们的假设，即 NBD1 处的 ATP 水解对于 MRP1 的 ATP 依赖性溶质转运可能不是必需的； 2. 测试NBD1和NBD2上核苷酸结合引起的构象变化是否足以将溶质转运穿过质膜； 3. 检验我们的假设，即两种 NBD 的核苷酸释放促进 MRP1 蛋白启动新的 ATP 依赖性溶质转运循环； 4.确定Km(ATP)、Vmax(LTC4)与耐药性的关系。从这些目标中获得的新见解可能为对抗与 MRP1 过度表达相关的 MDR 的新方法提供基础。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mutation of the aromatic amino acid interacting with adenine moiety of ATP to a polar residue alters the properties of multidrug resistance protein 1.

与 ATP 腺嘌呤部分相互作用的芳香族氨基酸突变为极性残基，改变了多药耐药蛋白 1 的特性。

DOI：
发表时间：
2004-11-19
期刊：
影响因子：
0
作者：
Zhao, Qing;Chang, Xiu
通讯作者：
Chang, Xiu

(R)- and (S)-verapamil differentially modulate the multidrug-resistant protein MRP1.

(R)-和(S)-维拉帕米差异调节多重耐药蛋白 MRP1。

DOI：
发表时间：
2007-10-26
期刊：
影响因子：
0
作者：
Perrotton, Thomas;Trompier, Doriane;Chang, Xiu;Di Pietro, Attilio;Baubichon
通讯作者：
Baubichon

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：
发表时间：
2004-07-15
期刊：
影响因子：
11.2
作者：
Trompier, Doriane;Chang, Xiu;Barattin, Régis;du Moulinet D'Hardemare, Amaury;Di Pietro, Attilio;Baubichon
通讯作者：
Baubichon

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.

核苷酸结合结构域2的H环中的残基与该位点的ATP和/或多药抗性蛋白MRP1的其他残基形成氢键在ATP依赖性溶质转运过程中起着至关重要的作用。