Induction of Apoptosis and Fas Receptor/Fas Ligand Expression by Ischemia/Reperfusion in Cardiac Myocytes Requires Serine 727 of the STAT-1 Transcription Factor but Not Tyrosine 701

Stephanou, Anastasis; Scarabelli, Tiziano M.; Brar, Bhawanjit K.; Nakanishi, Yoshinobu; Matsumura, Miho; Knight, Richard; Latchman, David S.

doi:10.1074/jbc.m101177200

Cited by 162 publications

(169 citation statements)

References 37 publications

(49 reference statements)

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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: 80%

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: 80%

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

et al. 2006

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“…We have shown that STAT-1 is expressed at enhanced levels following ischaemia/reoxygenation and is phosphorylated on tyrosine 701 and serine 727. 10,11 Moreover, inhibition of STAT-1 expression using an anti-sense approach protects the cardiac cells from apoptosis induced by ischaemia/reoxygenation. 10 To probe further the features of STAT-1 required for stress-induced apoptosis we have used the U3A cell line which lacks functional STAT-1.…”

Section: Introductionmentioning

confidence: 99%

The C-terminal activation domain of the STAT-1 transcription factor is necessary and sufficient for stress-induced apoptosis

2002

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It has previously been demonstrated that the STAT-1 transcription factor plays a key role in apoptosis induced by the cellular regulatory factors interferon g and TNF-a. Here we demonstrate that cells lacking STAT-1 show reduced cell death/apoptosis in response to stressful stimuli such as heat or ischaemia. Expression of STAT-1 in these cells does not enhance basal cell death but restores sensitivity to stressinduced death whereas this effect is not observed upon overexpression of STAT-3. Enhanced sensitivity to stress-induced cell death requires the C-terminal activation domain of STAT-1 and the phosphorylation sites at tyrosine 701 and serine 727. Moreover, we show for the first time in any system that the isolated C-terminal domain of STAT-1 is able to enhance stress-induced cell death in the absence of the DNA binding domain or any other region of STAT-1. Hence, STAT-1 plays a key role in stress-induced cell death, potentially acting via a novel co-activator-type mechanism and represents a possible therapeutic target for strategies aimed at minimising cell death, for example, following ischaemic injury.

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“…[18][19][20] For example, overexpression of STAT1 enhances apoptotic cell death in cardiac myocyte after ischemia-reperfusion, but STAT1 antisense manipulation reduces apoptosis and decreases STAT1-induced caspase 1 and apoptotic gene (FAS, FASL) promoter activity. 21,22 Further, overexpression of STAT1 inhibits the promoter activity of anti-apoptotic genes Bcl-2 and Bcl-XL . 23 STAT1 also induces apoptosis through interacting with p53 and enhanced expression of p53-regulated genes.…”

mentioning

confidence: 99%

A novel defense mechanism that is activated on amyloid-β insult to mediate cell survival: role of SGK1-STAT1/STAT2 signaling

et al. 2009

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Amyloid-b (Ab) is known to induce apoptotic cell death and its underlying mechanism has been studied extensively, but the endogenous protection mechanism that results from Ab insult is less known. In this study, we have found that Ab 1À42 produced a dose-dependent decrease in cell viability and dose-dependent increase in apoptotic cell death in PC12 cells. Meanwhile, Ab 1À42 (0.1 lM) increased the phosphorylation of serum-and glucocorticoid-inducible kinase1 (SGK1) at Ser-78 specifically. A parallel increase in ERK1/2, STAT1 and STAT2 phosphorylation and the anti-apoptotic gene Mcl-1 expression was also observed. Transfection of rat siRNAs against ERK1/2, SGK1, STAT1 and STAT2 abolished these effects of Ab. Transfection of sgkS78D, the constitutively active SGK1, dose-dependently protected against Ab-induced apoptosis and dose-dependently increased the expression of Mcl-1. SGK1 activation further phosphorylates STAT1 at Tyr-701 and Ser-727 directly, and activates STAT2 at The presence of senile plaque is a major pathological hallmark of Alzheimer's disease (AD) and amyloid-b peptides (Ab 1À40 , Ab 1À42 ) are the major components of senile plaque. Ab is generated from sequential and proteolytic cleavage of the amyloid precursor protein (APP) by b-and g-secretases. 1 Ab is known to cause lipid peroxidation, free radical production, caspase-3 activation, protein cleavage and DNA fragmentation that finally lead to apoptosis. [2][3][4] Ab also promotes the expression of some pro-inflammatory genes, such as cyclooxygenase-2 and interleukin-1b, and activation of these signalings would also result in apoptosis. 5 Further, Ab was shown to activate the p53 promoter and result in p53-dependent apoptosis. 6 On the other hand, when Ab produces its toxicity, cells would also develop defense mechanisms to cope with Ab toxicity. For example, a nonamyloidogenic neurotrophic peptide sAPPa is generated by a-secretase cleavage of APP and sAPPa is shown to activate neuroprotectin D1 to promote cell survival. 5 However, with the role and mechanism of Ab-induced toxicity been studied extensively, the endogenous rescue mechanism caused by Ab is less known.Serum-and glucocorticoid-inducible kinase 1 (SGK1) is a member of the serine/threonine protein kinase family that is induced transcriptionally by glucocorticoid and serum 7 and it governs a variety of cellular functions. 8 SGK1 is a downstream target of phosphatidylinositol 3-kinase (PI3-K) signaling. 9 SGK1 is directly phosphorylated by 3-phosphoinositidedependent protein kinase 1 (PDK1) at Thr-256 on SGK1 phosphorylation by PDK2 at Ser-422. 10 In addition, SGK1 is phosphorylated by p38 mitogen-activated protein kinase (p38 MAPK) at Ser-78 and p38 MAPK phosphorylation of SGK1 mediates cell survival in response to interleukin-6 stimulation. 11 In another study, SGK1 was shown to promote cell survival through phosphorylation and inactivation of the proapoptotic forkhead transcription factor FKHRL1. 12 Further, induction of SGK1 protects epithelial tumor cells from serum starvation-indu...

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Induction of Apoptosis and Fas Receptor/Fas Ligand Expression by Ischemia/Reperfusion in Cardiac Myocytes Requires Serine 727 of the STAT-1 Transcription Factor but Not Tyrosine 701

Cited by 162 publications

References 37 publications

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

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

The C-terminal activation domain of the STAT-1 transcription factor is necessary and sufficient for stress-induced apoptosis

A novel defense mechanism that is activated on amyloid-β insult to mediate cell survival: role of SGK1-STAT1/STAT2 signaling

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