title: Transport functions and physiological significance of 76 kDa Ral-binding GTPase activating protein (RLIP76).
abstract: We have recently demonstrated that a previously known Ral-binding GTPase activating protein, RLIP76, can also catalyze ATP-dependent transport of various structurally unrelated xeno- and endobiotics irrespective of their net charge (Awasthi et al., 2000, Biochemistry, 39: 9327). RLIP76 is a non-ATP binding cassette (ABC) protein but it has two ATP-binding sites and shows basal ATPase activity which is stimulated in the presence of its transport substrates (allocrites) such as doxorubicin (DOX) and S-(2,4-dinitrophenyl) glutathione (DNP-SG). Proteoliposomes reconstituted with purified RLIP76 catalyze ATP-dependent, saturable transport of DOX, as well as of glutathione-conjugates including leukotrienes (LTC4) and the GSH-conjugate of 4-hydroxynonenal (GS-HNE). In erythrocytes the majority of transport activity for DOX, GS-HNE, and LTC4 is accounted for by RLIP76. Cells exposed to mild oxidative stress show a rapid and transient induction of RLIP76 resulting in an increased efflux of GS-HNE and acquire resistance to oxidative stress mediated toxicity and apoptosis. Cells transfected with RLIP76 acquire resistance to DOX through increased efflux of the drug suggesting its possible role in the mechanisms of drug-resistance. In this article, we discuss the significance of transport functions of RLIP76 highlighting its role in the defense mechanisms against oxidative injury, and modulation of signaling mechanisms.
authors.affiliation: Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Awasthi
authors.forename: Rajendra
authors.initials: R
authors.lastname: Sharma
authors.forename: Yusong
authors.initials: Y
authors.lastname: Yang
authors.forename: Sharad S
authors.initials: SS
authors.lastname: Singhal
authors.forename: Slawomir
authors.initials: S
authors.lastname: Pikula
authors.forename: Joanna
authors.initials: J
authors.lastname: Bandorowicz-Pikula
authors.forename: Shivendra V
authors.initials: SV
authors.lastname: Singh
authors.forename: Piotr
authors.initials: P
authors.lastname: Zimniak
authors.forename: Yogesh C
authors.initials: YC
authors.lastname: Awasthi
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans
chemical_list: D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; D020690:GTPase-Activating Proteins; C095637:RALBP1 protein, human; D000251:Adenosine Triphosphatases