Zinc and the cytoskeleton in the neuronal modulation of transcription factor NFAT

Mackenzie, Gerardo G.; Oteiza, Patricia I.

doi:10.1002/jcp.20861

Cited by 34 publications

(46 citation statements)

References 56 publications

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“…Although a previous study has shown that the disruption of tubulin polymerization affects NFAT nuclear translocation in neural cells (13), the mode of the action remains unknown. Our present study identified the role of tubulin a as an adaptor in NFAT-importin b interaction.…”

Section: Resultsmentioning

confidence: 97%

Cutting Edge: Tubulin α Functions as an Adaptor in NFAT–Importin β Interaction

Ishiguro

Ando

Maeda

et al. 2011

The Journal of Immunology

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Upon T cell stimulation, NFAT is dephosphorylated by calcineurin, leading to nuclear translocation via NFAT–importin β interaction. Whereas the process of NFAT dephosphorylation has been well researched, the molecular mechanism of NFAT–importin β interaction remains unknown. In contrast to NF-κB and STAT, no importin α family members have been reported as adaptor proteins for NFAT. Our study shows that tubulin α, but not tubulin β, binds to the N-terminal region of NFAT containing the regulatory and Rel homology domains. Importin β interacts with the NFAT–tubulin α complex rather than NFAT or tubulin α alone, resulting in cotranslocation of NFAT and tubulin α into the nucleus. Furthermore, the interaction is suppressed by acetate-induced tubulin α acetylation at lysine 40. In conclusion, tubulin α functions as an adaptor in NFAT–importin β interaction, and this function is regulated by acetate-induced acetylation.

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Section: Resultsmentioning

confidence: 97%

Cutting Edge: Tubulin α Functions as an Adaptor in NFAT–Importin β Interaction

Ishiguro

Ando

Maeda

et al. 2011

The Journal of Immunology

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“…The specificity of NF-B's requirement for dyneinbased transport was tested by examining the effect of loss of endogenous dynein on the activity of two additional transcription factors, one which is largely localized in the nucleus (CREB) and another which undergoes cytoplasmic to nuclear translocation (NFAT). Interestingly, dynein knockdown did not significantly alter either CREB or NFAT reporter activity, although it has been reported that perturbations in the microtubule network could inhibit NFAT (32). While p53 is known to use dynein (26), the transport mechanisms of many nuclear localizing molecules are either unknown or are independent of the cytoskeleton (29,33,34).…”

Section: Discussionmentioning

confidence: 99%

Stimulated nuclear translocation of NF-κB and shuttling differentially depend on dynein and the dynactin complex

Shrum¹,

DeFrancisco

Meffert

2009

Proc. Natl. Acad. Sci. U.S.A.

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Translocation from the cytoplasm to the nucleus is required for the regulation of gene expression by transcription factors of the nuclear factor kappa B (NF-B) family. The p65:p50 NF-B heterodimer that predominates in many cell types can undergo stimulated movement, following degradation of the I B inhibitor, as well as shuttling in the absence of stimulation with I B bound. Disruption of the dynactin complex and knockdown of endogenous dynein were used to investigate the nuclear translocation requirements for stimulated and shuttling movement of NF-B. A differential dependence of these two modes of transport on the dynein molecular motor and dynactin was found. NF-B used active dynein-dependent transport following stimulation while translocation during shuttling was mediated by a dynein-independent pathway that could be potentiated by dynactin disruption, consistent with a process of facilitated diffusion. Nuclear translocation and activation of NF-B-dependent gene expression showed a dependence on endogenous dynein in a variety of cell types and in response to diverse activating stimuli, suggesting that dyneindependent transport of NF-B may be a conserved mechanism in the NF-B activation pathway and could represent a potential point of regulation.NF-kappaB ͉ nuclear transport ͉ transcription ͉ molecular motor ͉ active transport T he NF-B or Rel transcription factors are ubiquitouslyexpressed regulators of gene expression that are essential for physiological processes ranging from innate and adaptive immunity to learning and memory. NF-B functions as a dimer and is retained in a latent form in the cytoplasm, bound to the inhibitor of NF-B (I B). In the canonical pathway, incoming stimuli trigger activation of the I B-kinase complex (IKK) that phosphorylates I B␣ and leads to its degradation. The subsequent translocation of active I B-free NF-B from cytoplasm to nucleus is critical for NF-B-dependent gene expression. In the absence of I B degradation, NF-B can undergo stimulusindependent movement back and forth between the nucleus and cytoplasm in a process termed shuttling (1). Shuttling of p65:p50 NF-B dimers is believed to result from incomplete masking of the p50 nuclear localization sequence (NLS) by bound I B␣ and can be observed by blocking exportin1/crm1-mediated nuclear export under unstimulated conditions (2).While NF-B requires importin family members to cross the nuclear pore (3), the molecular mechanisms underlying NF-B cytoplasmic movement remain poorly understood. Studies examining the role of microtubules are conflicting, possibly because the pharmacological agents that disrupt microtubules result in a confounding activation of NF-B (4-10). Microtubule-dependent transport can also be probed by disrupting the multisubunit dynactin complex, and it was recently reported that dynactin could play a role in the nuclear accumulation of neuronal NF-B (10). Dynactin regulates the processivity of molecular motors using microtubules, including cytoplasmic dynein and kinesin (11,12). Dynein is a retrograde m...

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“…2). Zinc deficiency in cells and fetal brain increases NFAT activation but the nuclear translocation of NFAT is impaired due to disruption of the microtubule network leading to a subsequent reduction in NFAT-dependent gene expression (Aimo et al, 2010b;Mackenzie and Oteiza, 2007). These changes in cell signaling were also observed during marginal zinc deficiency (Aimo et al, 2010b).…”

Section: Cell-signaling Cascadesmentioning

confidence: 93%

Zinc and reproduction: effects of zinc deficiency on prenatal and early postnatal development

Uriu‐Adams

Keen

2010

Birth Defects Research Pt B

118

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A large body of evidence supports the concept that human pregnancy outcome is significantly influenced by the nutritional status of the mother. The consumption of "poor diets" has been associated with an increased risk for pregnancy complications, including gross structural birth defects, prematurity, low birth weight, and an increased risk for neurobehavioral and immunological abnormalities after birth. Forty-four years ago, zinc deficiency in mammals was shown to be teratogenic. Maternal zinc deficiency produces effects ranging from infertility and embryo/fetal death, to intrauterine growth retardation and teratogenesis. Postnatal complications of maternal zinc deficiency can also occur, and include behavioral abnormalities, impaired immunocompetence, and an elevated risk for high blood pressure in the offspring. It has been suggested that developmental zinc deficiency in humans can present a significant challenge to the conceptus, increasing the risk for numerous defects. Developmental zinc deficiency can occur through multiple pathways, and the concept that acute phase response-induced changes in maternal zinc metabolism may be a common cause of embryonic and fetal zinc deficiency is presented. Potential mechanisms underlying the teratogenic effects of zinc deficiency are reviewed. The potential value of maternal zinc supplementation in high risk pregnancies is discussed.

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Zinc and the cytoskeleton in the neuronal modulation of transcription factor NFAT

Cited by 34 publications

References 56 publications

Cutting Edge: Tubulin α Functions as an Adaptor in NFAT–Importin β Interaction

Cutting Edge: Tubulin α Functions as an Adaptor in NFAT–Importin β Interaction

Stimulated nuclear translocation of NF-κB and shuttling differentially depend on dynein and the dynactin complex

Zinc and reproduction: effects of zinc deficiency on prenatal and early postnatal development

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