Awasthi Yogesh C, Sharma Rajendra, Yadav Sushma, Dwivedi Seema, Sharma Abha, Awasthi Sanjay
Department of Biochemistry and Molecular Biology, 551-Basic Science Bldg., University of Texas Medical Branch at Galveston, Galveston, TX 77555-0647, USA.
Curr Drug Metab. 2007 May;8(4):315-23. doi: 10.2174/138920007780655414.
RLIP76 or Ral binding protein (RalBP-1) was initially cloned as a Ral-effector that was proposed as a link between Ral and Ras pathways. This protein is encoded in humans on chromosome 18p11.3 by a gene with 11 exons and 9 introns and is found ubiquitously from drosophila to humans. RLIP76 displays inhibitory GTPase activity toward Rho/Rac class G-protein cdc42 which is involved in regulation of cytoskeletal organization, lamellipodia, cell migration and apoptosis via Ras. We have recently shown that RLIP76 is also a multispecific transporter of chemotherapeutic agents and glutathione conjugates (GS-E). In human cells RLIP76 accounts for more than two third of the transport activity for GS-E and drugs as opposed to the ABC-transporters including MRP1, which account for less than one third of this activity. Evidence is mounting that RLIP76 is a stress-responsive multi-specific, non-ABC transporter which represents an entirely novel link between stress-inducible G-protein signaling, receptor tyrosine-kinase signaling, endocytosis, heat-shock and stress defense pathways, and transport mediated drug-resistance. The expression of RLIP76 is significantly greater in human cancer cells of diverse origin as compared to the non-malignant cells. Inhibition of RLIP76, using antibodies towards a cell surface epitope, or depletion of RLIP76 using either siRNA or anti-sense phosphorothioate oligonucleotides preferentially causes apoptosis in malignant cells. Administration of RLIP76 antibodies, siRNA, or anti-sense oligonucleotides to mice bearing syngeneic B16 mouse melanoma tumors causes rapid and complete regression of tumors. Studies summarized in this review strongly suggest that RLIP76 is a logical target for clinical intervention of not only multi-drug resistance but also for diseases resulting from oxidative stress.
RLIP76 或 Ral 结合蛋白（RalBP - 1）最初作为一种 Ral 效应蛋白被克隆，被认为是 Ral 与 Ras 信号通路之间的联系。该蛋白在人类中由位于 18 号染色体 p11.3 上的一个基因编码，该基因有 11 个外显子和 9 个内含子，从果蝇到人类广泛存在。RLIP76 对 Rho/Rac 类 G 蛋白 cdc42 具有抑制性 GTP 酶活性，cdc42 通过 Ras 参与细胞骨架组织、片状伪足、细胞迁移和凋亡的调节。我们最近发现 RLIP76 还是化疗药物和谷胱甘肽偶联物（GS - E）的多特异性转运体。在人类细胞中，RLIP76 占 GS - E 和药物转运活性的三分之二以上，而包括 MRP1 在内的 ABC 转运体占比不到三分之一。越来越多的证据表明 RLIP76 是一种应激反应性多特异性非 ABC 转运体，它代表了应激诱导的 G 蛋白信号传导、受体酪氨酸激酶信号传导、内吞作用、热休克和应激防御途径以及转运介导的耐药性之间全新的联系。与非恶性细胞相比，RLIP76 在多种来源的人类癌细胞中的表达明显更高。使用针对细胞表面表位的抗体抑制 RLIP76，或使用 siRNA 或反义硫代磷酸酯寡核苷酸耗尽 RLIP76，优先导致恶性细胞凋亡。给携带同基因 B16 小鼠黑色素瘤肿瘤的小鼠注射 RLIP76 抗体、siRNA 或反义寡核苷酸会导致肿瘤迅速完全消退。本综述总结的研究强烈表明，RLIP76 不仅是多药耐药临床干预的合理靶点，也是氧化应激所致疾病临床干预的合理靶点。
