Zinc deficiency affects the STAT1/3 signaling pathways in part through redox-mediated mechanisms

S. Supasai, L. Aimo, A. M. Adamo, Gerardo Mackenzie, P. I. Oteiza

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Zinc deficiency affects the development of the central nervous system (CNS) through mechanisms only partially understood. We previously showed that zinc deficiency causes CNS oxidative stress, damaging microtubules and impairing protein nuclear shuttling. STAT1 and STAT3 transcription factors, which require nuclear import for their functions, play major roles in CNS development. Thus, we investigated whether zinc deficiency disrupts STAT1 and STAT3 signaling pathways in the developing fetal CNS, characterizing the involvement of oxidative stress and the cytoskeleton in the adverse effects. Maternal (gestation day 0–19) marginal zinc deficiency (MZD) reduced STAT1 and STAT3 tyrosine phosphorylation and their nuclear translocation in the embryonic day 19 (E19) rat brain. Similar effects were observed in zinc depleted IMR-32 neuroblastoma cells, with an associated decrease in STAT1- and STAT3-dependent gene transactivation. Zinc deficiency caused oxidative stress (increased 4-hydroxynonenal-protein adducts) in E19 brain and IMR-32 cells, which was prevented in cells by supplementation with 0.5 mM α-lipoic acid (LA). In zinc depleted IMR-32 cells, the low tyrosine phosphorylation of STAT1, but not that of STAT3, recovered upon incubation with LA. STAT1 and STAT3 nuclear transports were also restored by LA. Accordingly, chemical disruption of the cytoskeleton partially reduced STAT1 and STAT3 nuclear levels. In summary, the redox-dependent tyrosine phosphorylation, and oxidant-mediated disruption of the cytoskeleton are involved in the deleterious effects of zinc deficit on STAT1 and STAT3 activation and nuclear translocation. Therefore, disruption of the STAT1 and STAT3 signaling pathways may in part explain the deleterious effects of maternal MZD on fetal brain development.

Original languageEnglish (US)
Pages (from-to)469-481
Number of pages13
JournalRedox Biology
Volume11
DOIs
StatePublished - Apr 1 2017

Fingerprint

Oxidation-Reduction
Zinc
Neurology
Thioctic Acid
Phosphorylation
Oxidative stress
Central Nervous System
Cytoskeleton
Tyrosine
Brain
Oxidative Stress
Cell Nucleus Active Transport
Mothers
STAT1 Transcription Factor
Microtubule Proteins
STAT3 Transcription Factor
Fetal Development
Neuroblastoma
Oxidants
Transcriptional Activation

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry

Cite this

Zinc deficiency affects the STAT1/3 signaling pathways in part through redox-mediated mechanisms. / Supasai, S.; Aimo, L.; Adamo, A. M.; Mackenzie, Gerardo; Oteiza, P. I.

In: Redox Biology, Vol. 11, 01.04.2017, p. 469-481.

Research output: Contribution to journalArticle

Supasai, S. ; Aimo, L. ; Adamo, A. M. ; Mackenzie, Gerardo ; Oteiza, P. I. / Zinc deficiency affects the STAT1/3 signaling pathways in part through redox-mediated mechanisms. In: Redox Biology. 2017 ; Vol. 11. pp. 469-481.
@article{3837665a7b4341638163c0dc35aa778a,
title = "Zinc deficiency affects the STAT1/3 signaling pathways in part through redox-mediated mechanisms",
abstract = "Zinc deficiency affects the development of the central nervous system (CNS) through mechanisms only partially understood. We previously showed that zinc deficiency causes CNS oxidative stress, damaging microtubules and impairing protein nuclear shuttling. STAT1 and STAT3 transcription factors, which require nuclear import for their functions, play major roles in CNS development. Thus, we investigated whether zinc deficiency disrupts STAT1 and STAT3 signaling pathways in the developing fetal CNS, characterizing the involvement of oxidative stress and the cytoskeleton in the adverse effects. Maternal (gestation day 0–19) marginal zinc deficiency (MZD) reduced STAT1 and STAT3 tyrosine phosphorylation and their nuclear translocation in the embryonic day 19 (E19) rat brain. Similar effects were observed in zinc depleted IMR-32 neuroblastoma cells, with an associated decrease in STAT1- and STAT3-dependent gene transactivation. Zinc deficiency caused oxidative stress (increased 4-hydroxynonenal-protein adducts) in E19 brain and IMR-32 cells, which was prevented in cells by supplementation with 0.5 mM α-lipoic acid (LA). In zinc depleted IMR-32 cells, the low tyrosine phosphorylation of STAT1, but not that of STAT3, recovered upon incubation with LA. STAT1 and STAT3 nuclear transports were also restored by LA. Accordingly, chemical disruption of the cytoskeleton partially reduced STAT1 and STAT3 nuclear levels. In summary, the redox-dependent tyrosine phosphorylation, and oxidant-mediated disruption of the cytoskeleton are involved in the deleterious effects of zinc deficit on STAT1 and STAT3 activation and nuclear translocation. Therefore, disruption of the STAT1 and STAT3 signaling pathways may in part explain the deleterious effects of maternal MZD on fetal brain development.",
author = "S. Supasai and L. Aimo and Adamo, {A. M.} and Gerardo Mackenzie and Oteiza, {P. I.}",
year = "2017",
month = "4",
day = "1",
doi = "10.1016/j.redox.2016.12.027",
language = "English (US)",
volume = "11",
pages = "469--481",
journal = "Redox Biology",
issn = "2213-2317",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - Zinc deficiency affects the STAT1/3 signaling pathways in part through redox-mediated mechanisms

AU - Supasai, S.

AU - Aimo, L.

AU - Adamo, A. M.

AU - Mackenzie, Gerardo

AU - Oteiza, P. I.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Zinc deficiency affects the development of the central nervous system (CNS) through mechanisms only partially understood. We previously showed that zinc deficiency causes CNS oxidative stress, damaging microtubules and impairing protein nuclear shuttling. STAT1 and STAT3 transcription factors, which require nuclear import for their functions, play major roles in CNS development. Thus, we investigated whether zinc deficiency disrupts STAT1 and STAT3 signaling pathways in the developing fetal CNS, characterizing the involvement of oxidative stress and the cytoskeleton in the adverse effects. Maternal (gestation day 0–19) marginal zinc deficiency (MZD) reduced STAT1 and STAT3 tyrosine phosphorylation and their nuclear translocation in the embryonic day 19 (E19) rat brain. Similar effects were observed in zinc depleted IMR-32 neuroblastoma cells, with an associated decrease in STAT1- and STAT3-dependent gene transactivation. Zinc deficiency caused oxidative stress (increased 4-hydroxynonenal-protein adducts) in E19 brain and IMR-32 cells, which was prevented in cells by supplementation with 0.5 mM α-lipoic acid (LA). In zinc depleted IMR-32 cells, the low tyrosine phosphorylation of STAT1, but not that of STAT3, recovered upon incubation with LA. STAT1 and STAT3 nuclear transports were also restored by LA. Accordingly, chemical disruption of the cytoskeleton partially reduced STAT1 and STAT3 nuclear levels. In summary, the redox-dependent tyrosine phosphorylation, and oxidant-mediated disruption of the cytoskeleton are involved in the deleterious effects of zinc deficit on STAT1 and STAT3 activation and nuclear translocation. Therefore, disruption of the STAT1 and STAT3 signaling pathways may in part explain the deleterious effects of maternal MZD on fetal brain development.

AB - Zinc deficiency affects the development of the central nervous system (CNS) through mechanisms only partially understood. We previously showed that zinc deficiency causes CNS oxidative stress, damaging microtubules and impairing protein nuclear shuttling. STAT1 and STAT3 transcription factors, which require nuclear import for their functions, play major roles in CNS development. Thus, we investigated whether zinc deficiency disrupts STAT1 and STAT3 signaling pathways in the developing fetal CNS, characterizing the involvement of oxidative stress and the cytoskeleton in the adverse effects. Maternal (gestation day 0–19) marginal zinc deficiency (MZD) reduced STAT1 and STAT3 tyrosine phosphorylation and their nuclear translocation in the embryonic day 19 (E19) rat brain. Similar effects were observed in zinc depleted IMR-32 neuroblastoma cells, with an associated decrease in STAT1- and STAT3-dependent gene transactivation. Zinc deficiency caused oxidative stress (increased 4-hydroxynonenal-protein adducts) in E19 brain and IMR-32 cells, which was prevented in cells by supplementation with 0.5 mM α-lipoic acid (LA). In zinc depleted IMR-32 cells, the low tyrosine phosphorylation of STAT1, but not that of STAT3, recovered upon incubation with LA. STAT1 and STAT3 nuclear transports were also restored by LA. Accordingly, chemical disruption of the cytoskeleton partially reduced STAT1 and STAT3 nuclear levels. In summary, the redox-dependent tyrosine phosphorylation, and oxidant-mediated disruption of the cytoskeleton are involved in the deleterious effects of zinc deficit on STAT1 and STAT3 activation and nuclear translocation. Therefore, disruption of the STAT1 and STAT3 signaling pathways may in part explain the deleterious effects of maternal MZD on fetal brain development.

UR - http://www.scopus.com/inward/record.url?scp=85008975655&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85008975655&partnerID=8YFLogxK

U2 - 10.1016/j.redox.2016.12.027

DO - 10.1016/j.redox.2016.12.027

M3 - Article

C2 - 28086195

AN - SCOPUS:85008975655

VL - 11

SP - 469

EP - 481

JO - Redox Biology

JF - Redox Biology

SN - 2213-2317

ER -