TY - JOUR
T1 - Glutathione S-Transferase P influences redox and migration pathways in bone marrow
AU - Zhang, Jie
AU - Ye, Zhi Wei
AU - Gao, Peng
AU - Reyes, Leticia
AU - Jones, Elizabeth E.
AU - Branham-O'Connor, Melissa
AU - Blumer, Joe B.
AU - Drake, Richard R.
AU - Manevich, Yefim
AU - Townsend, Danyelle M.
AU - Tew, Kenneth D.
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (CA08660, CA117259, NCRR P20RR024485-COBRE in Oxidants, Redox Balance and Stress Signaling) and support from the South Carolina Centers of Excellence program, and was conducted in a facility constructed with the support from the National Institutes of Health, Grant Number C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources. Supported in part by the Drug Metabolism and Clinical Pharmacology shared Resource, Hollings Cancer Center, Medical University of South Carolina. J.Z. was supported by the Swedish Research Council (No. 524-2011-6998). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2014 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2014/9
Y1 - 2014/9
N2 - To interrogate why redox homeostasis and glutathione S-transferase P (GSTP) are important in regulating bone marrow cell proliferation and migration, we isolated crude bone marrow, lineage negative and bone marrow derived-dendritic cells (BMDDCs) from both wild type (WT) and knockout (Gstp1/p2-/-) mice. Comparison of the two strains showed distinct thiol expression patterns. WT had higher baseline and reactive oxygen species-induced levels of S-glutathionylated proteins, some of which (sarco-endoplasmic reticulum Ca2+-ATPase) regulate Ca2+ fluxes and subsequently influence proliferation and migration. Redox status is also a crucial determinant in the regulation of the chemokine system. CXCL12 chemotactic response was stronger in WT cells, with commensurate alterations in plasma membrane polarization/permeability and intracellular calcium fluxes; activities of the downstream kinases, ERK and Akt were also higher in WT. In addition, expression levels of the chemokine receptor CXCR4 and its associated phosphatase, SHP-2, were higher in WT. Inhibition of CXCR4 or SHP2 decreased the extent of CXCL12-induced migration in WT BMDDCs. The differential surface densities of CXCR4, SHP-2 and inositol trisphosphate receptor in WT and Gstp1/p2-/-cells correlated with the differential CXCR4 functional activities, as measured by the extent of chemokine-induced directional migration and differences in intracellular signaling. These observed differences contribute to our understanding of how genetic ablation of GSTP causes higher levels of myeloproliferation and migration.
AB - To interrogate why redox homeostasis and glutathione S-transferase P (GSTP) are important in regulating bone marrow cell proliferation and migration, we isolated crude bone marrow, lineage negative and bone marrow derived-dendritic cells (BMDDCs) from both wild type (WT) and knockout (Gstp1/p2-/-) mice. Comparison of the two strains showed distinct thiol expression patterns. WT had higher baseline and reactive oxygen species-induced levels of S-glutathionylated proteins, some of which (sarco-endoplasmic reticulum Ca2+-ATPase) regulate Ca2+ fluxes and subsequently influence proliferation and migration. Redox status is also a crucial determinant in the regulation of the chemokine system. CXCL12 chemotactic response was stronger in WT cells, with commensurate alterations in plasma membrane polarization/permeability and intracellular calcium fluxes; activities of the downstream kinases, ERK and Akt were also higher in WT. In addition, expression levels of the chemokine receptor CXCR4 and its associated phosphatase, SHP-2, were higher in WT. Inhibition of CXCR4 or SHP2 decreased the extent of CXCL12-induced migration in WT BMDDCs. The differential surface densities of CXCR4, SHP-2 and inositol trisphosphate receptor in WT and Gstp1/p2-/-cells correlated with the differential CXCR4 functional activities, as measured by the extent of chemokine-induced directional migration and differences in intracellular signaling. These observed differences contribute to our understanding of how genetic ablation of GSTP causes higher levels of myeloproliferation and migration.
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U2 - 10.1371/journal.pone.0107478
DO - 10.1371/journal.pone.0107478
M3 - Article
C2 - 25216273
AN - SCOPUS:84929212907
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 9
M1 - e0107478
ER -