Stat3 confers resistance against hypoxia/reoxygenation-induced oxidative injury in hepatocytes through upregulation of Mn-SOD

Terui, Keita; Enosawa, Shin; Haga, Sanae; Zhang, Hui Qi; Kuroda, Hiroaki; Kouchi, Katsunori; Matsunaga, Tadashi; Yoshida, Hideo; Engelhardt, John F.; Irani, Kaikobad; Ohnuma, Naomi; Ozaki, Michitaka

doi:10.1016/j.jhep.2004.08.019

Cited by 70 publications

(65 citation statements)

References 51 publications

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“…Potential proapoptotic and significant prosurvival effects of STAT1 have been described previously (Shen et al, 2001;Stephanou and Latchman, 2003;Terui et al, 2004). Both effects were attributed to the ability of STAT1 to activate expression of either proapoptotic (Kumar et al, 1997;Stephanou et al, 2000Stephanou et al, , 2001 or prosurvival proteins (Stephanou et al, 1999;Madamanchi et al, 2001;Terui et al, 2004). We found here that in WT cells serine-phosphorylated STAT1 promotes cell survival through the regulation of expression of two known prosurvival genes, MCL-1 and HSP27 (Kabakov et al, 2003;Michels et al, 2005).…”

Section: Stat1 Is a Prosurvival Factor In Wilms' Tumorsupporting

confidence: 79%

“…Here we showed that S727-phosphorylated STAT1 promotes anchorage-independent growth of WT cells (Figure 2), probably by increasing cell survival under conditions of growth stress, such as hypoxia and starvation (Figure 3). Potential proapoptotic and significant prosurvival effects of STAT1 have been described previously (Shen et al, 2001;Stephanou and Latchman, 2003;Terui et al, 2004). Both effects were attributed to the ability of STAT1 to activate expression of either proapoptotic (Kumar et al, 1997;Stephanou et al, 2000Stephanou et al, , 2001 or prosurvival proteins (Stephanou et al, 1999;Madamanchi et al, 2001;Terui et al, 2004).…”

Section: Stat1 Is a Prosurvival Factor In Wilms' Tumormentioning

confidence: 74%

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Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

et al. 2006

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Wilms' tumor (WT), one of the most common pediatric solid cancers, arises in the developing kidney as a result of genetic and epigenetic changes that lead to the abnormal proliferation and differentiation of the metanephric blastema. As activation of signal transducers and activators of transcription (STATs) plays an important role in the maintenance/growth and differentiation of the metanephric blastema, and constitutively activated STATs facilitate neoplastic behaviors of a variety of cancers, we hypothesized that dysregulation of STAT signaling may also contribute to WT pathogenesis. Accordingly, we evaluated STAT phosphorylation patterns in tumors and found that STAT1 was constitutively phosphorylated on serine 727 (S727) in 19 of 21 primary WT samples and two WT cell lines. An inactivating mutation of S727 to alanine reduced colony formation of WT cells in soft agar by more than 80% and induced apoptosis under conditions of growth stress. S727-phosphorylated STAT1 provided apoptotic resistance for WT cells via upregulation of expression of the heat-shock protein (HSP)27 and antiapoptotic protein myeloid cell leukemia (MCL)-1. The kinase responsible for STAT1 S727 phosphorylation in WT cells was identified based upon the use of selective inhibitors as protein kinase CK2, not p38, MAP-kinase kinase (MEK)1/2, phosphatidylinositol 3 0 -kinase, protein kinase C or Ca/calmodulindependent protein kinase II (CaMKII). The inhibition of CK2 blocked the anchorage-independent growth of WT cells and induced apoptosis under conditions of growth stress. Our findings suggest that serine-phosphorylated STAT1, as a downstream target of protein kinase CK2, plays a critical role in the pathogenesis of WT and possibly other neoplasms with similar STAT1 phosphorylation patterns.

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Section: Stat1 Is a Prosurvival Factor In Wilms' Tumorsupporting

confidence: 79%

Section: Stat1 Is a Prosurvival Factor In Wilms' Tumormentioning

confidence: 74%

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

et al. 2006

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“…The signal transducer and activator of transcription (STAT)3 protein, has recently been identified as an important regulator of cell survival after exposure to apoptotic signals, including OS (10)(11)(12)(13)(14). The protective effect of STAT3 against apoptosis has been explained partly by upregulation of antiapoptotic proteins such as Bcl-XL and survivin as well as inactivation of caspases (12)(13)(14).…”

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confidence: 99%

“…The protective effect of STAT3 against apoptosis has been explained partly by upregulation of antiapoptotic proteins such as Bcl-XL and survivin as well as inactivation of caspases (12)(13)(14). It has been well established that OS induces the activation of various protein tyrosine kinases (PTK) but the PTK responsible for OS-mediated activation of STAT3 has not yet been identified (7,9,(15)(16)(17).…”

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confidence: 99%

STAT3 is a substrate of SYK tyrosine kinase in B-lineage leukemia/lymphoma cells exposed to oxidative stress

Uckun

Qazi

et al. 2010

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

127

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We provide unprecedented genetic and biochemical evidence that the antiapoptotic transcription factor STAT3 serves as a substrate for SYK tyrosine kinase both in vitro and in vivo. Induction of SYK in an ecdysone-inducible mammalian expression system results in STAT3 activation, as documented by tyrosine phosphorylation and nuclear translocation of STAT3, as well as amplified expression of several STAT3 target genes. STAT3 activation after oxidative stress (OS) is strongly diminished in DT40 chicken B-lineage lymphoma cells rendered SYK-deficient by targeted disruption of the syk gene. Introduction of a wild-type, C-terminal or N-terminal SH2 domain-mutated, but not a kinase domain-mutated, syk gene into SYK-deficient DT40 cells restores OS-induced enhancement of STAT-3 activity. Thus, SYK plays an important and indispensable role in OS-induced STAT3 activation and its catalytic SH1 domain is critical for this previously unknown regulatory function. These results provide evidence for the existence of a novel mode of cytokineindependent cross-talk that operates between SYK and STAT3 pathways and regulates apoptosis during OS. We further provide experimental evidence that SYK is capable of associating with and phosphorylating STAT3 in human B-lineage leukemia/lymphoma cells challenged with OS. In agreement with a prerequisite role of SYK in OS-induced STAT3 activation, OS does not induce tyrosine phosphorylation of STAT3 in SYK-deficient human proB leukemia cells. Notably, inhibition of SYK with a small molecule drug candidate prevents OS-induced activation of STAT3 and overcomes the resistance of human B-lineage leukemia/lymphoma cells to OSinduced apoptosis.apoptosis | cancer | radiation

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“…Furthermore, we found that the transcription factor signal transducer and activator of transcription (STAT)3 was undetectable at 0 h but rapidly induced by 8 h of hypoxia in HPAECs, whereas STAT5B was reduced between 0 and 8 h of hypoxia. STAT3 has been shown to be involved in the protective cellular response to hypoxic injury (47) and is involved in the hypoxia-inducible factor (HIF)-1␣-dependent induction of VEGF in renal (25) and prostate carcinoma cells (18). STAT5B has recently been shown to be involved in cell proliferation in vascular endothelial cells (13).…”

Section: Exposure To Hypoxia Results In An Antiproliferative Phenotypmentioning

confidence: 99%

Comparative SAGE analysis of the response to hypoxia in human pulmonary and aortic endothelial cells

Peters

Ning

Chu

et al. 2006

Physiological Genomics

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(SAGE) to analyze the temporal response of human pulmonary artery endothelial cells (HPAECs) to short-term chronic hypoxia at the level of transcription. Primary cultures of HPAECs were exposed to 1% O2 hypoxia for 8 and 24 h and compared with identical same-passage cells cultured under standard (5% CO2-95% air) conditions. Hierarchical clustering of significant hypoxia-responsive genes identified temporal changes in the expressions of a number of well-described gene families including those encoding proteins involved in thrombosis, stress response, apoptosis, angiogenesis, and cell proliferation. These experiments build on previously published data describing the transcriptomic response of human aortic endothelial cells (HAECs) obtained from the same donor and cultured under identical conditions, and we have thus taken advantage of the immortality of SAGE data to make direct comparisons between these two data sets. This approach revealed comprehensive information relating to the similarities and differences at the level of mRNA expression between HAECs and HPAECs. For example, we found differences in the cell type-specific response to hypoxia among genes encoding cytoskeletal factors, including paxillin, and proteins involved in metabolic energy production, the response to oxidative stress, and vasoreactivity (e.g., endothelin-1). These efforts contribute to the expanding collection of publicly available SAGE data and provide a foundation on which to base further efforts to understand the characteristics of the vascular response to hypoxia in the pulmonary circulation relative to systemic vasculature.transcriptome; temporal; serial analysis of gene expression HYPOXIA is an important pathological stimulus that has profound effects on the vasculature. These include alteration of vascular tone, coagulant function, redox homeostasis, endothelial permeability, and cell proliferation. Significantly, the response to hypoxia is different in distinct vascular beds. Hypoxia elicits systemic vasodilation, yet causes acute pulmonary vasoconstriction, which, if sustained, leads to profound remodeling of the pulmonary vasculature and culminates in structural-based increases in pulmonary vascular resistance and the subsequent development of pulmonary hypertension (30,33,36).Although the focus of intense research for nearly a century, the mechanisms underlying these differential vascular responses to hypoxia remain unclear (55). It has, however, been previously noted that fundamental molecular differences exist between the response of pulmonary and systemic vascular cells to hypoxia (19), but little information exists regarding the differences in the genome-wide response to hypoxic stress between pulmonary and systemic vascular endothelial cells.Despite the intense interest in the cellular response to hypoxia, particularly in the context of vascular biology, there have been few systematic attempts to document the transcriptional response to hypoxia in primary vascular endothelial cells. We (40) previously utilized serial ana...

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Stat3 confers resistance against hypoxia/reoxygenation-induced oxidative injury in hepatocytes through upregulation of Mn-SOD

Cited by 70 publications

References 51 publications

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

STAT3 is a substrate of SYK tyrosine kinase in B-lineage leukemia/lymphoma cells exposed to oxidative stress

Comparative SAGE analysis of the response to hypoxia in human pulmonary and aortic endothelial cells

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