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PMID: 9857197 Published · ppublish English Journal Article

Crm1p mediates regulated nuclear export of a yeast AP-1-like transcription factor.

The EMBO journal ·Vol. 17 ·No. 24 ·1998-12-15 ·Pages 7416-29

Yan C, Lee LH, Davis LI

Abstract

The yeast AP-1-like transcription factor, Yap1p, activates genes required for the response to oxidative stress. Yap1p is normally cytoplasmic and inactive, but will activate by nuclear translocation if cells are placed in an oxidative environment. Here we show that Yap1p is a target of the beta-karyopherin-like nuclear exporter, Crm1p. Yap1p is constitutively nuclear in a crm1 mutant, and Crm1p binds to a nuclear export sequence (NES)-like sequence in Yap1p in the presence of RanGTP. Recognition of Yap1p by Crm1p is inhibited by oxidation, and this inhibition requires at least one of the three cysteine residues flanking the NES. These results suggest that Yap1p localization is largely regulated at the level of nuclear export, and that the oxidation state affects the accessibility of the Yap1p NES to Crm1p directly. We also show that a mutation in RanGAP (rna1-1) is synthetically lethal with crm1 mutants. Yap1p export is inhibited in both rna1-1 and prp20 (RanGNRF) mutant strains, but Yap1p rapidly accumulates at the nuclear periphery after shifting rna1-1, but not other mutant cells to the non-permissive temperature. Thus, disassembly of export complexes in response to RanGTP hydrolysis may be required for release of substrate from a terminal binding site at the nuclear pore complex (NPC).

MeSH Terms
Amino Acid Sequence Biological Transport Carrier Proteins/genetics,metabolism Cell Compartmentation Cell Nucleus/metabolism Cytoplasm/metabolism DNA-Binding Proteins/metabolism Guanosine Triphosphate/metabolism Immunoblotting Karyopherins Molecular Sequence Data Mutation Nuclear Proteins/metabolism Oxidation-Reduction Precipitin Tests Protein Binding Receptors, Cytoplasmic and Nuclear Saccharomyces cerevisiae Proteins Schizosaccharomyces/genetics,metabolism Transcription Factor AP-1 Transcription Factors/metabolism ran GTP-Binding Protein
Chemicals
Carrier Proteins DNA-Binding Proteins Karyopherins Nuclear Proteins Receptors, Cytoplasmic and Nuclear Saccharomyces cerevisiae Proteins Transcription Factor AP-1 Transcription Factors YAP1 protein, S cerevisiae exportin 1 protein Guanosine Triphosphate ran GTP-Binding Protein
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Yan C
W.M.Keck Institute for Cellular Visualization, Rosenstiel Center and Department of Biology, MS 029, Brandeis University, 415 South Street, Waltham, MA 02453, USA.
Lee L H
Davis L I
References (90)
90 references, click to expand
  1. RNA1 encodes a GTPase-activating protein specific for Gsp1p, the Ran/TC4 homologue of Saccharomyces cerevisiae.
    J Biol Chem. 1995 May 19;270(20):11860-5 PMID: 7744835
  2. Identification of a yeast karyopherin heterodimer that targets import substrate to mammalian nuclear pore complexes.
    J Biol Chem. 1995 Jul 14;270(28):16499-502 PMID: 7622450
  3. Two different subunits of importin cooperate to recognize nuclear localization signals and bind them to the nuclear envelope.
    Curr Biol. 1995 Apr 1;5(4):383-92 PMID: 7627554
  4. Identification of a signal for rapid export of proteins from the nucleus.
    Cell. 1995 Aug 11;82(3):463-73 PMID: 7634336
  5. The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs.
    Cell. 1995 Aug 11;82(3):475-83 PMID: 7543368
  6. Distinct functions for the two importin subunits in nuclear protein import.
    Nature. 1995 Sep 21;377(6546):246-8 PMID: 7675110
  7. Kinetics of spindle pole body separation in budding yeast.
    Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9707-11 PMID: 7568202
  8. GTP hydrolysis by Ran occurs at the nuclear pore complex in an early step of protein import.
    J Cell Biol. 1995 Nov;131(3):571-81 PMID: 7593180
  9. Transcriptional control by protein phosphorylation: signal transmission from the cell surface to the nucleus.
    Curr Biol. 1995 Jul 1;5(7):747-57 PMID: 7583121
  10. Protein import into nuclei: association and dissociation reactions involving transport substrate, transport factors, and nucleoporins.
    Cell. 1995 Dec 1;83(5):683-92 PMID: 8521485
  11. Caffeine-resistance in fission yeast is caused by mutations in a single essential gene, crm1+.
    Mol Gen Genet. 1996 Jan 15;250(1):59-68 PMID: 8569688
  12. The human T-cell leukemia virus type 1 posttranscriptional trans-activator Rex contains a nuclear export signal.
    J Virol. 1996 Sep;70(9):6442-5 PMID: 8709278
  13. Cytoplasmic localization of mitogen-activated protein kinase kinase directed by its NH2-terminal, leucine-rich short amino acid sequence, which acts as a nuclear export signal.
    J Biol Chem. 1996 Aug 16;271(33):20024-8 PMID: 8702720
  14. Kap104p: a karyopherin involved in the nuclear transport of messenger RNA binding proteins.
    Science. 1996 Oct 25;274(5287):624-7 PMID: 8849456
  15. Identification of different roles for RanGDP and RanGTP in nuclear protein import.
    EMBO J. 1996 Oct 15;15(20):5584-94 PMID: 8896452
  16. Exportin 1 (Crm1p) is an essential nuclear export factor.
    Cell. 1997 Sep 19;90(6):1041-50 PMID: 9323132
  17. CRM1 is an export receptor for leucine-rich nuclear export signals.
    Cell. 1997 Sep 19;90(6):1051-60 PMID: 9323133
  18. Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor.
    Cell. 1997 Sep 19;90(6):1061-71 PMID: 9323134
  19. Transport into and out of the cell nucleus.
    EMBO J. 1998 May 15;17(10):2721-7 PMID: 9582265
  20. Nuclear export of cyclin B1 and its possible role in the DNA damage-induced G2 checkpoint.
    EMBO J. 1998 May 15;17(10):2728-35 PMID: 9582266
  21. Regulation of the fission yeast transcription factor Pap1 by oxidative stress: requirement for the nuclear export factor Crm1 (Exportin) and the stress-activated MAP kinase Sty1/Spc1.
    Genes Dev. 1998 May 15;12(10):1453-63 PMID: 9585505
  22. Nuclear protein import, but not mRNA export, is defective in all Saccharomyces cerevisiae mutants that produce temperature-sensitive forms of the Ran GTPase homologue Gsp1p.
    Mol Gen Genet. 1998 Apr;257(6):624-34 PMID: 9604885
  23. Ran binding domains promote the interaction of Ran with p97/beta-karyopherin, linking the docking and translocation steps of nuclear import.
    J Biol Chem. 1996 Feb 2;271(5):2357-60 PMID: 8576188
  24. Amphibian transcription factor IIIA proteins contain a sequence element functionally equivalent to the nuclear export signal of human immunodeficiency virus type 1 Rev.
    Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2936-40 PMID: 8610146
  25. RAN/TC4 mutants identify a common requirement for snRNP and protein import into the nucleus.
    J Cell Biol. 1996 May;133(3):485-94 PMID: 8636225
  26. Protein sequence requirements for function of the human T-cell leukemia virus type 1 Rex nuclear export signal delineated by a novel in vivo randomization-selection assay.
    Mol Cell Biol. 1996 Aug;16(8):4207-14 PMID: 8754820
  27. In vivo nuclear transport kinetics in Saccharomyces cerevisiae.
    Methods Cell Biol. 1998;53:545-57 PMID: 9348524
  28. The importin-beta family member Crm1p bridges the interaction between Rev and the nuclear pore complex during nuclear export.
    Curr Biol. 1997 Oct 1;7(10):767-75 PMID: 9368759
  29. CRM1 is responsible for intracellular transport mediated by the nuclear export signal.
    Nature. 1997 Nov 20;390(6657):308-11 PMID: 9384386
  30. The asymmetric distribution of the constituents of the Ran system is essential for transport into and out of the nucleus.
    EMBO J. 1997 Nov 3;16(21):6535-47 PMID: 9351834
  31. Inhibition of mRNA export in vertebrate cells by nuclear export signal conjugates.
    Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14394-9 PMID: 9405623
  32. A distinct and parallel pathway for the nuclear import of an mRNA-binding protein.
    J Cell Biol. 1997 Dec 29;139(7):1645-53 PMID: 9412460
  33. A nuclear import pathway for a protein involved in tRNA maturation.
    J Cell Biol. 1997 Dec 29;139(7):1655-61 PMID: 9412461
  34. RanBP1 is crucial for the release of RanGTP from importin beta-related nuclear transport factors.
    FEBS Lett. 1997 Dec 15;419(2-3):249-54 PMID: 9428644
  35. The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins.
    EMBO J. 1998 Jan 2;17(1):288-96 PMID: 9427762
  36. Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein.
    EMBO J. 1998 Jan 15;17(2):554-64 PMID: 9430646
  37. Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300.
    EMBO J. 1998 Feb 16;17(4):1087-95 PMID: 9463386
  38. Nuclear localization of the C2H2 zinc finger protein Msn2p is regulated by stress and protein kinase A activity.
    Genes Dev. 1998 Feb 15;12(4):586-97 PMID: 9472026
  39. ICP27 mediates HSV RNA export by shuttling through a leucine-rich nuclear export signal and binding viral intronless RNAs through an RGG motif.
    Genes Dev. 1998 Mar 15;12(6):868-79 PMID: 9512520
  40. Identification of a nuclear export receptor for tRNA.
    Curr Biol. 1998 Mar 12;8(6):305-14 PMID: 9512417
  41. Regulation of a nuclear export signal by an adjacent inhibitory sequence: the effector domain of the influenza virus NS1 protein.
    Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):4864-9 PMID: 9560194
  42. Transport of macromolecules between the nucleus and the cytoplasm.
    RNA. 1998 Apr;4(4):351-64 PMID: 9630243
  43. Leptomycin B-sensitive nuclear export of MAPKAP kinase 2 is regulated by phosphorylation.
    EMBO J. 1998 Jun 15;17(12):3363-71 PMID: 9628873
  44. Nuclear-cytoplasmic shuttling of C-ABL tyrosine kinase.
    Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7457-62 PMID: 9636171
  45. Identification of a tRNA-specific nuclear export receptor.
    Mol Cell. 1998 Feb;1(3):359-69 PMID: 9660920
  46. Snurportin1, an m3G-cap-specific nuclear import receptor with a novel domain structure.
    EMBO J. 1998 Jul 15;17(14):4114-26 PMID: 9670026
  47. Control of cyclin B1 localization through regulated binding of the nuclear export factor CRM1.
    Genes Dev. 1998 Jul 15;12(14):2131-43 PMID: 9679058
  48. Leptomycin B inhibition of signal-mediated nuclear export by direct binding to CRM1.
    Exp Cell Res. 1998 Aug 1;242(2):540-7 PMID: 9683540
  49. Transportin: nuclear transport receptor of a novel nuclear protein import pathway.
    Exp Cell Res. 1996 Dec 15;229(2):261-6 PMID: 8986607
  50. Ran-binding protein 1 (RanBP1) forms a ternary complex with Ran and karyopherin beta and reduces Ran GTPase-activating protein (RanGAP) inhibition by karyopherin beta.
    J Biol Chem. 1997 Jan 3;272(1):551-5 PMID: 8995296
  51. Characterization of the nuclear protein import mechanism using Ran mutants with altered nucleotide binding specificities.
    EMBO J. 1996 Dec 16;15(24):7120-8 PMID: 9003787
  52. The Saccharomyces cerevisiae AP-1 protein discriminates between oxidative stress elicited by the oxidants H2O2 and diamide.
    J Biol Chem. 1997 Mar 21;272(12):7908-14 PMID: 9065458
  53. Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3.
    Science. 1997 Mar 28;275(5308):1930-4 PMID: 9072970
  54. Mutations in the nuclear export signal of human ran-binding protein RanBP1 block the Rev-mediated posttranscriptional regulation of human immunodeficiency virus type 1.
    J Biol Chem. 1997 Apr 25;272(17):11356-60 PMID: 9111043
  55. Regulation of yAP-1 nuclear localization in response to oxidative stress.
    EMBO J. 1997 Apr 1;16(7):1710-20 PMID: 9130715
  56. Karyopherin beta2 mediates nuclear import of a mRNA binding protein.
    Proc Natl Acad Sci U S A. 1997 May 13;94(10):5055-60 PMID: 9144189
  57. A distinct nuclear import pathway used by ribosomal proteins.
    Cell. 1997 May 30;89(5):715-25 PMID: 9182759
  58. Requirement of guanosine triphosphate-bound ran for signal-mediated nuclear protein export.
    Science. 1997 Jun 20;276(5320):1842-4 PMID: 9188526
  59. Nuclear import of hnRNP A1 is mediated by a novel cellular cofactor related to karyopherin-beta.
    J Cell Sci. 1997 Jun;110 ( Pt 11):1325-31 PMID: 9202393
  60. A novel class of RanGTP binding proteins.
    J Cell Biol. 1997 Jul 14;138(1):65-80 PMID: 9214382
  61. Disassembly of RanGTP-karyopherin beta complex, an intermediate in nuclear protein import.
    J Biol Chem. 1997 Aug 1;272(31):19538-46 PMID: 9235958
  62. Evidence for a role of CRM1 in signal-mediated nuclear protein export.
    Science. 1997 Oct 3;278(5335):141-4 PMID: 9311922
  63. Transformation of intact yeast cells treated with alkali cations.
    J Bacteriol. 1983 Jan;153(1):163-8 PMID: 6336730
  64. 5-Fluoroorotic acid as a selective agent in yeast molecular genetics.
    Methods Enzymol. 1987;154:164-75 PMID: 3323810
  65. Rapid and efficient site-specific mutagenesis without phenotypic selection.
    Methods Enzymol. 1987;154:367-82 PMID: 3323813
  66. Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase.
    Gene. 1988 Jul 15;67(1):31-40 PMID: 3047011
  67. The yeast RNA1 gene product necessary for RNA processing is located in the cytosol and apparently excluded from the nucleus.
    J Cell Biol. 1990 Aug;111(2):309-21 PMID: 2116418
  68. Use of a screen for synthetic lethal and multicopy suppressee mutants to identify two new genes involved in morphogenesis in Saccharomyces cerevisiae.
    Mol Cell Biol. 1991 Mar;11(3):1295-305 PMID: 1996092
  69. Catalysis of guanine nucleotide exchange on Ran by the mitotic regulator RCC1.
    Nature. 1991 Nov 7;354(6348):80-2 PMID: 1944575
  70. The yeast SRM1 protein and human RCC1 protein share analogous functions.
    Cell Regul. 1991 Oct;2(10):781-92 PMID: 1666302
  71. The PAR1 (YAP1/SNQ3) gene of Saccharomyces cerevisiae, a c-jun homologue, is involved in oxygen metabolism.
    Curr Genet. 1992 Apr;21(4-5):269-73 PMID: 1525853
  72. Fission yeast pap1-dependent transcription is negatively regulated by an essential nuclear protein, crm1.
    Mol Cell Biol. 1992 Dec;12(12):5474-84 PMID: 1448080
  73. Nuclear PRP20 protein is required for mRNA export.
    EMBO J. 1993 Jan;12(1):233-41 PMID: 7679070
  74. A simple and efficient method for direct gene deletion in Saccharomyces cerevisiae.
    Nucleic Acids Res. 1993 Jul 11;21(14):3329-30 PMID: 8341614
  75. Yeast bZip proteins mediate pleiotropic drug and metal resistance.
    J Biol Chem. 1993 Sep 5;268(25):18850-8 PMID: 8360174
  76. The GTP-binding protein Ran/TC4 is required for protein import into the nucleus.
    Nature. 1993 Oct 14;365(6447):661-3 PMID: 8413630
  77. Cdi1, a human G1 and S phase protein phosphatase that associates with Cdk2.
    Cell. 1993 Nov 19;75(4):791-803 PMID: 8242750
  78. Multiple regions of NSR1 are sufficient for accumulation of a fusion protein within the nucleolus.
    J Cell Biol. 1993 Dec;123(5):1081-91 PMID: 8245119
  79. Inhibition of nuclear protein import by nonhydrolyzable analogues of GTP and identification of the small GTPase Ran/TC4 as an essential transport factor.
    J Cell Biol. 1993 Dec;123(6 Pt 2):1649-59 PMID: 8276887
  80. YAP1 dependent activation of TRX2 is essential for the response of Saccharomyces cerevisiae to oxidative stress by hydroperoxides.
    EMBO J. 1994 Feb 1;13(3):655-64 PMID: 8313910
  81. Stress-induced transcriptional activation mediated by YAP1 and YAP2 genes that encode the Jun family of transcriptional activators in Saccharomyces cerevisiae.
    Mol Gen Genet. 1994 Feb;242(3):250-6 PMID: 8107671
  82. Leptomycin B targets a regulatory cascade of crm1, a fission yeast nuclear protein, involved in control of higher order chromosome structure and gene expression.
    J Biol Chem. 1994 Mar 4;269(9):6320-4 PMID: 8119981
  83. Genetic and physical interactions between Srp1p and nuclear pore complex proteins Nup1p and Nup2p.
    J Cell Biol. 1994 Aug;126(3):619-30 PMID: 8045927
  84. Yap1p, a yeast transcriptional activator that mediates multidrug resistance, regulates the metabolic stress response.
    EMBO J. 1994 Sep 1;13(17):4036-41 PMID: 8076599
  85. A functional interaction between Rev and yeast pre-mRNA is related to splicing complex formation.
    EMBO J. 1994 Sep 1;13(17):4096-104 PMID: 8076605
  86. Brefeldin A sensitivity and resistance in Schizosaccharomyces pombe. Isolation of multiple genes conferring resistance.
    J Biol Chem. 1994 Sep 30;269(39):24229-36 PMID: 7929079
  87. nup1 mutants exhibit pleiotropic defects in nuclear pore complex function.
    J Cell Biol. 1994 Oct;127(2):319-32 PMID: 7929578
  88. Isolation of a protein that is essential for the first step of nuclear protein import.
    Cell. 1994 Dec 2;79(5):767-78 PMID: 8001116
  89. Human RanGTPase-activating protein RanGAP1 is a homologue of yeast Rna1p involved in mRNA processing and transport.
    Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1749-53 PMID: 7878053
  90. Previously identified protein of uncertain function is karyopherin alpha and together with karyopherin beta docks import substrate at nuclear pore complexes.
    Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2008-11 PMID: 7892216
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/17.24.7416
Published
1998-12-15
Pages
7416-29
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1171086
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/17.24.7416 PMC Full Text View journal details
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