Cloning and characterization of the human glutathione synthetase 5′-flanking region

Lee, Taunia D.; Yang, Heping; Whang, Janet; Lu, Shelly C.

doi:10.1042/bj20050439

Cited by 64 publications

(45 citation statements)

References 34 publications

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“…The promoter of the GSH synthetase gene contains multiple binding sites for STAT family members including STAT5, suggesting that STAT5 might regulate the transcriptional activation of this gene. 42 Moreover, the synthesis of GSH or the activity of antioxidant enzymes such as GSH reductase and GSH peroxidase are modulated by the Hsp27 and Hsp70. Thus, it is likely that STAT5 modulates expression or activity of these enzymes via an indirect effect on Hsp27 and Hsp70 expression.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells

Cholez

Debuysscher

Bourgeais³

et al. 2012

Leukemia

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,5,6 STAT5 transcription factors are involved in normal B lymphocyte development and in leukemogenesis. We show that the inhibition of STAT5A expression or activity in the NALM6, 697 and Reh leukemic pre-B cell lines, results in a higher spontaneous apoptosis and an increased FAS-induced cell death. However, the molecular mechanisms underlying the altered pre-B cell survival are unclear. We used a proteomic approach to identify proteins that are differentially regulated in cells expressing (NALM6D5A) or not a dominant negative form of STAT5A. Among the 14 proteins identified, six were involved in the control of the oxidative stress like glutathione (GSH) synthetase and DJ-1. Accordingly, we showed increased levels of reactive oxygen species (ROS) in NALM6D5A cells and suppression of the increased sensitivity to Fas-mediated apoptosis by the GSH tripeptide. Similar results were observed when NALM6 cells were treated with TAT-STAT5D5A fusion proteins or STAT5A shRNA. In addition, the 697 and Reh pre-B cells were found to share number of molecular changes observed in NALM6D5A cells including ROS generation, following inhibition of STAT5 expression or function. Our results point out to a hitherto undescribed link between STAT5 and oxidative stress and provide new insights into STAT5 functions and their roles in leukemogenesis.Leukemia ( INTRODUCTIONThe signal transducer and activator of transcription factors STAT5A and STAT5B are two closely related STAT family members that play a major role in cytokine and growth factor signaling. 1 Number of studies have demonstrated that STAT5 plays a crucial role in hematopoiesis. In particular, the knockout mice models (Stat5a/ b DN/DN and Stat5a/b null/null ) have pointed up the important role of STAT5 in hematopoietic cell development. 2,3 These mice have multiple hematopoietic defects, which affect the proliferation and/ or survival of both myeloid and lymphoid lineages, including B-cell development. 4 In the Stat5a/b null/null mice, the precursor B-cell compartment is substantially reduced presumably due to an inability of progenitor B cells to proliferate in response to interleukin-7 (IL-7). However, differentiation towards mature B cells seems to be unaffected. 5,6 STAT5 is also involved in the regulation of IL-7-dependent germline transcription, histone acetylation and DNA recombination of distal VH gene segments, which are the hallmark of B lymphocyte development. 7 Accordingly, a constitutively active form of STAT5B in IL-7R À / À mice, is sufficient to restore B-cell development. 8 However, the instructive role for STAT5 and IL-7-R signaling in early B-cell development has been controversial in a mouse model of conditional mutagenesis of STAT5. 9 This model showed that the main role of IL-7-mediated activation of STAT5 is to promote pro-B-cell survival via Mcl1 and to prevent premature rearrangements of the immunoglobulin-k light-chain locus (Igk) by binding to the

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Section: Discussionmentioning

confidence: 99%

Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells

Cholez

Debuysscher

Bourgeais³

et al. 2012

Leukemia

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“…Accumulating evidence shows that Nrf2 activation can consequently elevate the expression and enzymatic activities of ␥-glutamyl-cysteine synthetase/GST as well as the GSH level in cells (56,57). Considering the reversible nature of sulfhydryl modification by sulforaphane, the elevated GSH levels may favor the restoration of NES TA activity and trigger Nrf2 nuclear export.…”

Section: Discussionmentioning

confidence: 99%

Nrf2 Possesses a Redox-sensitive Nuclear Exporting Signal in the Neh5 Transactivation Domain

Li¹,

Yu²,

Kong

2006

Journal of Biological Chemistry

141

135

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“…The rat GCLM promoter also has a functional ARE element (−295 to −285) (Yang et al, 2005b). This ARE element is important for basal promoter activity as well as TNFα-mediated induction of rat GCLM (Yang et al, 2005). AP-1, NFκB and Nrf2 are all positive regulators of the rat GCLM gene and are induced by TNFα treatment (Yang et al, 2005b).…”

Section: Regulation Of Gcl Modifier Subunit (Gclm)-mentioning

confidence: 99%

“…The gene encoding GS was cloned in 1995 (Huang et al, 1995) but its transcriptional regulation has only been characterized recently after cloning of the rat and human GS promoters Lee et al, 2005). 1,10-phenanthroline, a metal chelating agent, was reported to induce GS expression but the mechanism was not examined (Sun, 1997).…”

Section: Regulation Of Glutathione Synthase (Gs)mentioning

confidence: 99%

Regulation of glutathione synthesis

Lu¹

2009

Molecular Aspects of Medicine

1,559

765

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Glutathione (GSH) is a ubiquitous intracellular peptide with diverse functions that include detoxification, antioxidant defense, maintenance of thiol status, and modulation of cell proliferation. GSH is synthesized in the cytosol of all mammalian cells in a tightly regulated manner. The major determinants of GSH synthesis are the availability of cysteine, the sulfur amino acid precursor, and the activity of the rate-limiting enzyme, glutamate cysteine ligase (GCL). GCL is composed for a catalytic (GCLC) and modifier (GCLM) subunit and they are regulated at multiple levels and at times differentially. The second enzyme of GSH synthesis, GSH synthase (GS) is also regulated in a coordinated manner as GCL subunits and its up-regulation can further enhance the capacity of the cell to synthesize GSH. Oxidative stress is well known to induce the expression of GSH synthetic enzymes. Key transcription factors identified thus far include Nrf2/Nrf1 via the antioxidant response element (ARE), activator protein-1 (AP-1) and nuclear factor κ B (NFκB). Dysregulation of GSH synthesis is increasingly being recognized as contributing to the pathogenesis of many pathological conditions. These include diabetes mellitus, pulmonary fibrosis, cholestatic liver injury, endotoxemia and drug-resistant tumor cells. Manipulation of the GSH synthetic capacity is an important target in the treatment of many of these disorders.

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Cloning and characterization of the human glutathione synthetase 5′-flanking region

Cited by 64 publications

References 34 publications

Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells

Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells

Nrf2 Possesses a Redox-sensitive Nuclear Exporting Signal in the Neh5 Transactivation Domain

Regulation of glutathione synthesis

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