RLIP76: A novel glutathione-conjugate and multi-drug transporter.
RLIP76, a stress-responsive, multi-functional protein with multi-specific transport activity towards glutathione-conjugates (GS-E) and chemotherapeutic agents, is frequently over-expressed in malignant cells. Our recent studies suggest that it plays a prominent anti-apoptotic role selectively in cancer cells. We have previously shown that RLIP76 accounts for up to 80% of the transport of GS-E and blocking the RLIP76-mediated transport of GS-E in cells results in the accumulation of pro-apoptotic endogenous electrophiles and on-set of apoptosis. Here we demonstrate that when RLIP76 mediate transport of GS-E is abrogated either by anti-RLIP76 IgG or accumulation of 4-hydroxynonenal (4-HNE) and its GSH-conjugate (GS-HNE) occurs and a massive apoptosis is observed in cells, indicate that the inhibition of RLIP76 transport activity at the cell surface is sufficient for observed anti-tumor activity. RLIP76 is linked with certain cellular functions including membrane plasticity and movement (as a primary 'effector' in the Ral pathway, perhaps functioning as a GTPase activating protein, or GAP), and as a component of clathrin-coated pit-mediated receptor-ligand endocytosis-a process that mediates movement of membrane vesicles.
Singhal
Sharad S
SS
Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. ssinghal@hsc.unt.edu
Yadav
Sushma
S
Roth
Cherice
C
Singhal
Jyotsana
J
D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D018432:Drug Resistance, Multiple; D004705:Endocytosis; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D011487:Protein Conformation; D051571:Protein Kinase C-alpha / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D000447:Aldehydes; D020690:GTPase-Activating Proteins; C095637:RALBP1 protein, human; D051571:Protein Kinase C-alpha; D005978:Glutathione; C027576:4-hydroxy-2-nonenal