title: A pathway linking oxidative stress and the Ran GTPase system in progeria.
abstract: Maintaining the Ran GTPase at a proper concentration in the nucleus is important for nucleocytoplasmic transport. Previously we found that nuclear levels of Ran are reduced in cells from patients with Hutchinson-Gilford progeria syndrome (HGPS), a disease caused by constitutive attachment of a mutant form of lamin A (termed progerin) to the nuclear membrane. Here we explore the relationship between progerin, the Ran GTPase, and oxidative stress. Stable attachment of progerin to the nuclear membrane disrupts the Ran gradient and results in cytoplasmic localization of Ubc9, a Ran-dependent import cargo. Ran and Ubc9 disruption can be induced reversibly with H2O2. CHO cells preadapted to oxidative stress resist the effects of progerin on Ran and Ubc9. Given that HGPS-patient fibroblasts display elevated ROS, these data suggest that progerin inhibits nuclear transport via oxidative stress. A drug that inhibits pre-lamin A cleavage mimics the effects of progerin by disrupting the Ran gradient, but the effects on Ran are observed before a substantial ROS increase. Moreover, reducing the nuclear concentration of Ran is sufficient to induce ROS irrespective of progerin. We speculate that oxidative stress caused by progerin may occur upstream or downstream of Ran, depending on the cell type and physiological setting.
authors: Center for Cell Signaling, Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22903.
authors: Sutirtha
authors: S
authors: Datta
authors: Chelsi J
authors: CJ
authors: Snow
authors: Bryce M
authors: BM
authors: Paschal
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003412:Cricetulus; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D005347:Fibroblasts; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D034904:Lamin Type A; D061466:Lopinavir / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial; D009685:Nuclear Envelope / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D011371:Progeria / Q000473:pathology*; D011485:Protein Binding; D011498:Protein Precursors / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D058207:Sumoylation; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*; D020931:ran GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; C120587:RAN protein, human; D034741:RNA, Small Interfering; C090764:prelamin A; D061466:Lopinavir; D006861:Hydrogen Peroxide; D044763:Ubiquitin-Conjugating Enzymes; D020931:ran GTP-Binding Protein; D000098843:Ubiquitin-Conjugating Enzyme UBC9