Dissecting the Signaling Events That Impact Classical Nuclear Import and Target Nuclear Transport Factors

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2009 Dec 31

PMID 20041180

Citations 22

Authors

Mohamed Kodiha

Dan Tran

Andreea Morogan

Cynthia Qian

Ursula Stochaj

Affiliations

Soon will be listed here.

Abstract

Background: Signaling through MEK-->ERK1/2 and PI3 kinases is implicated in many aspects of cell physiology, including the survival of oxidant exposure. Oxidants play a role in numerous physiological and pathophysiological processes, many of which rely on transport in and out of the nucleus. However, how oxidative stress impacts nuclear trafficking is not well defined.

Methodology/principal Findings: To better understand the effect of stress on nucleocytoplasmic trafficking, we exposed cells to the oxidant diethyl maleate. This treatment activated MEK-->ERK1/2 as well as PI3 kinase-->Akt cascades and triggered the inhibition of classical nuclear import. To define the molecular mechanisms that regulate nuclear transport, we examined whether MEK and PI3 kinase signaling affected the localization of key transport factors. Using recently developed tools for image acquisition and analysis, the subcellular distributions of importin-alpha, CAS, and nucleoporins Nup153 and Nup88 were quantified in different cellular compartments. These studies identified specific profiles for the localization of transport factors in the nucleus and cytoplasm, and at the nuclear envelope. Our results demonstrate that MEK and PI3 kinase signaling as well as oxidative stress control nuclear trafficking and the localization of transport components. Furthermore, stress not only induced changes in transport factor distribution, but also upregulated post-translational modification of transport factors. Our results are consistent with the idea that the phosphorylation of importin-alpha, CAS, Nup153, and Nup88, and the O-GlcNAc modification of Nup153 increase when cells are exposed to oxidant.

Conclusions/significance: Our studies defined the complex regulation of classical nuclear import and identified key transport factors that are targeted by stress, MEK, and PI3 kinase signaling.

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References

Lee B, Cao R, Choi Y, Cho H, Rhee A, Hah C . The CREB/CRE transcriptional pathway: protection against oxidative stress-mediated neuronal cell death. J Neurochem. 2009; 108(5):1251-65. PMC: 2884273. DOI: 10.1111/j.1471-4159.2008.05864.x. View

Czubryt M, Austria J, Pierce G . Hydrogen peroxide inhibition of nuclear protein import is mediated by the mitogen-activated protein kinase, ERK2. J Cell Biol. 2000; 148(1):7-16. PMC: 2156210. DOI: 10.1083/jcb.148.1.7. View

Shaw R, Cantley L . Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006; 441(7092):424-30. DOI: 10.1038/nature04869. View

Jones D . Radical-free biology of oxidative stress. Am J Physiol Cell Physiol. 2008; 295(4):C849-68. PMC: 2575825. DOI: 10.1152/ajpcell.00283.2008. View

Zachara N, ODonnell N, Cheung W, Mercer J, Marth J, Hart G . Dynamic O-GlcNAc modification of nucleocytoplasmic proteins in response to stress. A survival response of mammalian cells. J Biol Chem. 2004; 279(29):30133-42. DOI: 10.1074/jbc.M403773200. View

Bastos R, Lin A, Enarson M, Burke B . Targeting and function in mRNA export of nuclear pore complex protein Nup153. J Cell Biol. 1996; 134(5):1141-56. PMC: 2120979. DOI: 10.1083/jcb.134.5.1141. View

Velloso L, Folli F, Perego L, Saad M . The multi-faceted cross-talk between the insulin and angiotensin II signaling systems. Diabetes Metab Res Rev. 2006; 22(2):98-107. DOI: 10.1002/dmrr.611. View

Griffis E, Craige B, Dimaano C, Ullman K, Powers M . Distinct functional domains within nucleoporins Nup153 and Nup98 mediate transcription-dependent mobility. Mol Biol Cell. 2004; 15(4):1991-2002. PMC: 379293. DOI: 10.1091/mbc.e03-10-0743. View

Kalas W, Kisielow P, Strzadala L . Inhibition of MEK induces fas expression and apoptosis in lymphomas overexpressing Ras. Leuk Lymphoma. 2002; 43(7):1469-74. DOI: 10.1080/1042819022386815. View

10.

Droge W . Free radicals in the physiological control of cell function. Physiol Rev. 2002; 82(1):47-95. DOI: 10.1152/physrev.00018.2001. View

11.

Kodiha M, Chu A, Matusiewicz N, Stochaj U . Multiple mechanisms promote the inhibition of classical nuclear import upon exposure to severe oxidative stress. Cell Death Differ. 2004; 11(8):862-74. DOI: 10.1038/sj.cdd.4401432. View

12.

Chu C, Plowey E, Wang Y, Patel V, Jordan-Sciutto K . Location, location, location: altered transcription factor trafficking in neurodegeneration. J Neuropathol Exp Neurol. 2007; 66(10):873-83. PMC: 2220049. DOI: 10.1097/nen.0b013e318156a3d7. View

13.

Riddick G, Macara I . A systems analysis of importin-{alpha}-{beta} mediated nuclear protein import. J Cell Biol. 2005; 168(7):1027-38. PMC: 2171841. DOI: 10.1083/jcb.200409024. View

14.

Castillo E, Ayte J, Chiva C, Moldon A, Carrascal M, Abian J . Diethylmaleate activates the transcription factor Pap1 by covalent modification of critical cysteine residues. Mol Microbiol. 2002; 45(1):243-54. DOI: 10.1046/j.1365-2958.2002.03020.x. View

15.

Weis K . Regulating access to the genome: nucleocytoplasmic transport throughout the cell cycle. Cell. 2003; 112(4):441-51. DOI: 10.1016/s0092-8674(03)00082-5. View

16.

Behrens P, Brinkmann U, Wellmann A . CSE1L/CAS: its role in proliferation and apoptosis. Apoptosis. 2003; 8(1):39-44. DOI: 10.1023/a:1021644918117. View

17.

Schulte D, Burkhart R, Musahl C, Hu B, Schlatterer C, Hameister H . Expression, phosphorylation and nuclear localization of the human P1 protein, a homologue of the yeast Mcm 3 replication protein. J Cell Sci. 1995; 108 ( Pt 4):1381-9. DOI: 10.1242/jcs.108.4.1381. View

18.

Matsuura Y, Stewart M . Structural basis for the assembly of a nuclear export complex. Nature. 2004; 432(7019):872-7. DOI: 10.1038/nature03144. View

19.

Miyamoto Y, Saiwaki T, Yamashita J, Yasuda Y, Kotera I, Shibata S . Cellular stresses induce the nuclear accumulation of importin alpha and cause a conventional nuclear import block. J Cell Biol. 2004; 165(5):617-23. PMC: 2172376. DOI: 10.1083/jcb.200312008. View

20.

Goldfarb D, Corbett A, Mason D, Harreman M, Adam S . Importin alpha: a multipurpose nuclear-transport receptor. Trends Cell Biol. 2004; 14(9):505-14. DOI: 10.1016/j.tcb.2004.07.016. View