ABC Transporters in Human Disease and Multidrug Resistan

人类疾病和多重耐药性中的 ABC 转运蛋白

• 批准号: 7289915
• 负责人: MICHAEL DEAN
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7289915
• 关键词: ABC; Transporters; Human; Disease; Multidrug

The ATP-binding cassette (ABC) gene family encodes a diverse group of transporter proteins that pump a wide variety of compounds across the membranes of cells and tissues. Several human ABC transporters are overexpressed in tumor cells that are resistant to chemotherapy drugs. We have demonstrated that the ABCA3 gene is mutated in children with neonatal respiratory failure. These patients have defects in the production of lung surfactant, a lipid rich secretion produced by alveolal type II cells. Mildly affected patients were identified that have missense mutations that may be partially functional. A new member of the ABC family has been characterized, ABCC13. This gene is a pseudogene in apes, but is a functional gene in the dog and monkey genomes. We have also characterized the ABCA14, ABCA15, and ABCA16 genes in the mouse genome. These genes are exclusively expressed in the testes. Analysis of mutations in the ABCG2 gene, an important drug transporter, reveals residues that are involved in the dimerization of the protein. ABCG2 is expressed as a transporter, and dimmers must form to generate a functional protein. Drugs that inhibit this transporter, or its dimerization could be used to inhibit the growth of cancer cells, and might be particularly useful against cancer stem cells.

ATP结合盒（ABC）基因家族编码了各种各样的转运蛋白，这些蛋白会在细胞和组织的整个膜上泵送各种化合物。几种人类ABC转运蛋白在抗化疗药物具有抗性药物中过表达。我们已经证明，新生儿呼吸衰竭儿童中ABCA3基因已突变。这些患者在肺表面活性剂的产生中存在缺陷，肺表面活性剂是由肺泡II型细胞产生的富含脂质的分泌。鉴定出有可能部分功能性的错义突变的患者。 ABC家族的一个新成员ABCC13。该基因是猿类中的假基因，但是狗和猴子基因组中的功能基因。我们还表征了小鼠基因组中的ABCA14，ABCA15和ABCA16基因。这些基因在睾丸中仅表达。对ABCG2基因（一种重要的药物转运蛋白）突变的分析揭示了与蛋白质二聚化有关的残基。 ABCG2表示为转运蛋白，必须形成调光片以生成功能性蛋白质。抑制该转运蛋白或其二聚化的药物可用于抑制癌细胞的生长，并且可能对癌症干细胞特别有用。