Glutathione S-transferase P influences redox and migration pathways in bone marrow.

Jie Zhang,Elizabeth E Jones,Joe B Blumer,Danyelle M Townsend,Leticia Reyes,Zhi-Wei Ye,Peng Gao,Kenneth D Tew,Richard R Drake,Melissa Branham-O’Connor,Yefim Manevich,Thomas Dittmar

doi:10.1371/journal.pone.0107478

Jie Zhang, Elizabeth E Jones + Show 10 more

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https://doi.org/10.1371/journal.pone.0107478

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Journal: PloS one	Publication Date: Sep 12, 2014
Citations: 53	License type: CC BY 4.0

Affiliation: Medical University of South Carolina

Abstract

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.

Highlights

The bone marrow produces all the differentiated hematopoietic cells for peripheral blood
We undertook a series of studies to determine how various bone marrow cell types from Gstp1/p22/2 mice differed from their wild type (WT) counterparts
Because reactive oxygen species (ROS) conditions have direct influence on cellular redox homeostasis, a number of thiol-dependent pathways are implicated, and these downstream targets are influenced by the presence/absence of Glutathione S-transferase P (GSTP)

Summary

Introduction

The bone marrow produces all the differentiated hematopoietic cells for peripheral blood This tissue is extremely sensitive to alterations in redox homeostasis, as proliferation and differentiation are influenced by physiological changes in a number of factors that are sensitive to reactive oxygen species (ROS; [1,2]). Glutathione S-transferase P (GSTP) is one of a family of GST isozymes and has functions as a catalytic enzyme, protein chaperone, kinase regulator and in regulating the forward reaction of protein S-glutathionylation [1,9]. This post-translational modification occurs in certain protein clusters that have roles in events regulating cell proliferation [10]. It is reasonable to speculate that the difference in ROS levels in myeloid progenitor and quiescent hematopoietic stem cells (HSCs) may act in intracellular signaling events that drive HSC differentiation and that modulation of redox-sensitive cysteines through S-glutathionylation may have a key role in these events

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