title: A Drosophila ABC transporter regulates lifespan.
abstract: MRP4 (multidrug resistance-associated protein 4) is a member of the MRP/ABCC subfamily of ATP-binding cassette (ABC) transporters that are essential for many cellular processes requiring the transport of substrates across cell membranes. Although MRP4 has been implicated as a detoxification protein by transport of structurally diverse endogenous and xenobiotic compounds, including antivirus and anticancer drugs, that usually induce oxidative stress in cells, its in vivo biological function remains unknown. In this study, we investigate the biological functions of a Drosophila homolog of human MRP4, dMRP4. We show that dMRP4 expression is elevated in response to oxidative stress (paraquat, hydrogen peroxide and hyperoxia) in Drosophila. Flies lacking dMRP4 have a shortened lifespan under both oxidative and normal conditions. Overexpression of dMRP4, on the other hand, is sufficient to increase oxidative stress resistance and extend lifespan. By genetic manipulations, we demonstrate that dMRP4 is required for JNK (c-Jun NH2-terminal kinase) activation during paraquat challenge and for basal transcription of some JNK target genes under normal condition. We show that impaired JNK signaling is an important cause for major defects associated with dMRP4 mutations, suggesting that dMRP4 regulates lifespan by modulating the expression of a set of genes related to both oxidative resistance and aging, at least in part, through JNK signaling.
authors.affiliation: Department of Pediatrics (Division of Respiratory Medicine), University of California San Diego, La Jolla, California, United States of America.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Pediatrics (Division of Respiratory Medicine), University of California San Diego, La Jolla, California, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu-Bo
authors.affiliation: Department of Pediatrics (Division of Respiratory Medicine), University of California San Diego, La Jolla, California, United States of America; Rady Children's Hospital San Diego, San Diego, California, United States of America.
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Haddad
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology; D000375:Aging / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D004330:Drosophila / Q000235:genetics* / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D006801:Humans; D008136:Longevity / Q000235:genetics*; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; D029721:Drosophila Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C520727:MRP4 protein, Drosophila