Nucleocytoplasmic trafficking of proteins: With or without Ran?

Stochaj, Ursula; Rother, Katherine L.

doi:10.1002/(sici)1521-1878(199907)21:7<579::aid-bies6>3.0.co;2-e

Cited by 36 publications

(26 citation statements)

References 81 publications

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“…The soluble factors Ran and importin-b as well as the nucleoporin Nup153 are essential components of the classical nuclear import apparatus (reviewed in Stochaj and Rother, 11 Gö rlich and Kutay 12 and Kü nzler and Hurt 15 ). Importantly, hydrogen peroxide treatment of HeLa cells interferes with the formation of the Ran concentration gradient (Figure 2A, d; 2B).…”

Section: Oxidants Redistribute Nuclear Transport Factorsmentioning

confidence: 99%

“…Like cytoplasmic transport factors, nucleoporins are involved in nucleocytoplasmic trafficking of proteins and RNA (reviewed in Stochaj and Rother, 11 Gö rlich and Kutay 12 and Kuersten et al 13 ). For instance, Nup153, a member of the FXFG family of nucleoporins, is located at the nuclear basket, where it participates in the termination of classical nuclear protein import.…”

Section: Introductionmentioning

confidence: 99%

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Multiple mechanisms promote the inhibition of classical nuclear import upon exposure to severe oxidative stress

et al. 2004

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In growing HeLa cells, severe stress elicited by the oxidant hydrogen peroxide inhibits classical nuclear import. Oxidant treatment collapses the nucleocytoplasmic Ran concentration gradient, thereby elevating cytoplasmic GTPase levels. The Ran gradient dissipates in response to a stress-induced depletion of RanGTP and a decreased efficiency of Ran nuclear import. In addition, oxidative stress induces a relocation of the nucleoporin Nup153 as well as the nuclear carrier importin-b, and docking of the importin-a/b/cargo complex at the nuclear envelope is reduced. Moreover, Ran, importin-b and Nup153 undergo proteolysis upon oxidative stress. Caspases and the proteasome degrade Ran and importin-b; however, ubiquitination of these transport factors is not observed. Inhibition of caspases in stressed cells alleviates the mislocalization of importin-b, but does not restore the Ran concentration gradient or classical import. In summary, inhibition of classical nuclear import by hydrogen peroxide is caused by a combination of multiple mechanisms that target different components of the transport apparatus.

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Section: Oxidants Redistribute Nuclear Transport Factorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multiple mechanisms promote the inhibition of classical nuclear import upon exposure to severe oxidative stress

et al. 2004

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“…A previous study has shown that deletion of a region encompassing the GATA-3 NLS region (aa 249 -311) prevents nuclear localization of the overexpressed protein (11). The affinity of the importin-␣-NLS interaction is a critical parameter in determining nuclear transport efficiency and may be influenced directly by phosphorylation (13,15,17).…”

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confidence: 99%

Regulation of Th2 Cytokine Genes by p38 MAPK-Mediated Phosphorylation of GATA-3

Maneechotesuwan

Yao

Ito

et al. 2007

The Journal of Immunology

150

111

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GATA-3 plays a critical role in allergic diseases by regulating the release of cytokines from Th2 lymphocytes. However, the molecular mechanisms involved in the regulation of GATA-3 in human T lymphocytes are not yet understood. Using small interfering RNA to knock down GATA-3, we have demonstrated its critical role in regulating IL-4, IL-5, and IL-13 release from a human T cell line. Specific stimulation of T lymphocytes by costimulation of CD3 and CD28 to mimic activation by APCs induces translocation of GATA-3 from the cytoplasm to the nucleus, with binding to the promoter region of Th2 cytokine genes, as determined by chromatin immunoprecipitation. GATA-3 nuclear translocation is dependent on its phosphorylation on serine residues by p38 MAPK, which facilitates interaction with the nuclear transporter protein importin-α. This provides a means whereby allergen exposure leads to the expression of Th2 cytokines, and this novel mechanism may provide new approaches to treating allergic diseases.

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“…7). One of the most intriguing of these involves the movement of calmodulin across the nuclear pore (8 -10).…”

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confidence: 99%

The High Mobility Group Box Transcription Factor Nhp6Ap Enters the Nucleus by a Calmodulin-dependent, Ran-independent Pathway

Hanover

Love

DeAngelis

et al. 2007

Journal of Biological Chemistry

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A gradient of Ran⅐GTP typically regulates traffic through the nuclear pore by modulating association of receptors with cargo.However, here we demonstrate that the yeast high mobility group box transcription factor Nhp6Ap enters the nucleus via a novel nuclear localization signal recognized by calcium calmodulin in a process that does not require Ran. Calmodulin is strictly required for the nondiffusional nuclear entry of Nhp6Ap. Calmodulin and DNA exhibit mutually exclusive binding to NHP6A, indicating that the directionality of Nhp6Ap nuclear accumulation may be driven by DNA-dependent dissociation of calmodulin. Our findings demonstrate that calmodulin can serve as a molecular switch triggering nuclear entry with subsequent dissociation of calmodulin binding upon interaction of cargo with chromatin. This pathway appears to be evolutionarily conserved; mammalian high mobility group box transcription factors often have two nuclear localization signals: one a classical Ran-dependent signal and a second that binds calmodulin. The finding that Nhp6Ap nuclear entry requires calmodulin but not Ran indicates that Nhp6Ap is a good model for studying this poorly understood but evolutionarily conserved calmodulin-dependent nuclear import pathway.Proteins enter the nucleus through nuclear pore complexes (NPCs).2 Those smaller than ϳ40 -50 kDa can traverse these pores by passive diffusion (1-5). Many larger proteins require soluble receptors, termed importins or karyopherins, which bind cargo in the cytoplasm, accompany it through the NPC, and release it in the nucleus. Most cargo proteins contain short nuclear localization signals (NLS), motifs recognized by the various receptor proteins.The small GTPase Ran drives the accumulation of cargo proteins in the nucleus by regulating the association and dissociation of NLS-containing proteins with importin/karyopherins.In the nucleus, most Ran is GTP-bound, whereas it is largely GDP-bound in the cytoplasm. Cargo proteins bind importins in the presence of Ran-GDP in the cytoplasm, and when an importin bound to cargo arrives in the nucleus, Ran-GTP induces cargo release (6). Thus, the Ran⅐GTP gradient across the NPC drives the accumulation of most NLS-containing cargo in the nucleus.Some Ran-independent nuclear import pathways have been described, although most remain poorly understood (for review see Ref. 7). One of the most intriguing of these involves the movement of calmodulin across the nuclear pore (8 -10). Calmodulin nuclear import was argued to be a facilitated mechanism that was blocked by the calmodulin antagonist peptide M13 and did not require cytosolic factors or an ATP-regenerating system (8, 10). In the presence of calcium, calmodulin was also shown to be able to facilitate movement of large molecules into the nucleus. This latter property suggested a Ca 2ϩ -inducible nuclear import function for calmodulin that might operate during cellular activation. The calmodulin-mediated pathway was proposed to be redundant with the canonic Ran⅐GTP-driven nuclear entry pathway...

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Nucleocytoplasmic trafficking of proteins: With or without Ran?

Cited by 36 publications

References 81 publications

Multiple mechanisms promote the inhibition of classical nuclear import upon exposure to severe oxidative stress

Multiple mechanisms promote the inhibition of classical nuclear import upon exposure to severe oxidative stress

Regulation of Th2 Cytokine Genes by p38 MAPK-Mediated Phosphorylation of GATA-3

The High Mobility Group Box Transcription Factor Nhp6Ap Enters the Nucleus by a Calmodulin-dependent, Ran-independent Pathway

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