CREB mediates ERK-induced survival of mouse renal tubular cells after oxidant stress

Arany, István; Megyesi, Judit; Reusch, Jane E.B.; Safirstein, Robert

doi:10.1111/j.1523-1755.2005.00569.x

Cited by 52 publications

(52 citation statements)

References 41 publications

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“…During I/R injury, the EGFR is activated in the proximal tubules of the kidney, but ERK activation is absent, and the proximal tubules undergo necrotic death (20,21). We made a similar observation in vitro: a high dose of H 2 O 2 causes necrotic (oncotic) death of renal proximal tubule cells with concomitant activation of the EGFR but not ERK, and ectopic activation of endogenous ERK rescues the cells from injury (14,15). On the other hand, during moderate stress (moderate dose of H 2 O 2 ) in vitro, renal proximal tubule cells survive through activation of the EGFR and ERK (14,15).…”

supporting

confidence: 49%

“…We made a similar observation in vitro: a high dose of H 2 O 2 causes necrotic (oncotic) death of renal proximal tubule cells with concomitant activation of the EGFR but not ERK, and ectopic activation of endogenous ERK rescues the cells from injury (14,15). On the other hand, during moderate stress (moderate dose of H 2 O 2 ) in vitro, renal proximal tubule cells survive through activation of the EGFR and ERK (14,15). These observations suggest that the activated EGFR could serve a prodeath function (22) in addition to its more widely accepted role of enhancing regeneration of the injured segments of the kidney (20,23,43,44).…”

mentioning

confidence: 95%

“…We sought means to manipulate either expression or Ser 36 phosphorylation of p66 shc to restore ERK activation and survival. Cell Lines and Animals-The immortalized mouse proximal tubule line TKPTS was used as described (14,15). Oxidative stress was induced by treatment of semiconfluent cells with 0.5 or 1 mM H 2 O 2 for various time points.…”

mentioning

confidence: 99%

“…Oxidative stress was induced by treatment of semiconfluent cells with 0.5 or 1 mM H 2 O 2 for various time points. For in vivo experiments, 129Sv mice were used, and I/R injury was induced as described (14,15).…”

mentioning

confidence: 99%

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p66 Inhibits Pro-survival Epidermal Growth Factor Receptor/ERK Signaling during Severe Oxidative Stress in Mouse Renal Proximal Tubule Cells

Arany

Faisal

Nagamine

et al. 2008

Journal of Biological Chemistry

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The fully executed epidermal growth factor receptor (EGFR)/ Ras/MEK/ERK pathway serves a pro-survival role in renal epithelia under moderate oxidative stress. We and others have demonstrated that during severe oxidative stress, however, the activated EGFR is disconnected from ERK activation in cultured renal proximal tubule cells and also in renal proximal tubules after ischemia/reperfusion injury, resulting in necrotic death. Studies have shown that the tyrosine-phosphorylated p46/52 isoforms of the ShcA family of adaptor proteins connect the activated EGFR to activation of Ras and ERK, whereas the p66 shc isoform can inhibit this p46/52 shc function. Here, we determined that severe oxidative stress (after a brief period of activation) terminates activation of the Ras/MEK/ERK pathway, which coincides with ERK/JNK-dependent Ser 36 phosphorylation of p66shc . Isoform-specific knockdown of p66 shc or mutation of Ser 36 to Ala, but not to Asp, attenuated severe oxidative stress-mediated ERK inhibition and cell death in vitro. Also, severe oxidative stress (unlike ligand stimulation and moderate oxidative stress, both of which support survival) increased binding of p66 shc to the activated EGFR and Grb2. This binding dissociated the SOS1 adaptor protein from the EGFR-recruited signaling complex, leading to termination of Ras/MEK/ERK activation. Notably, Ser 36 phosphorylation of p66 shc and its increased binding to the EGFR also occurred in the kidney after ischemia/reperfusion injury in vivo. At the same time, SOS1 binding to the EGFR declined, similar to the in vitro findings. Thus, the mechanism we propose in vitro offers a means to ameliorate oxidative stress-induced cell injury by either inhibiting Ser 36 phosphorylation of p66 shc or knocking down p66 shc expression in vivo.

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confidence: 49%

mentioning

confidence: 95%

mentioning

confidence: 99%

mentioning

confidence: 99%

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p66 Inhibits Pro-survival Epidermal Growth Factor Receptor/ERK Signaling during Severe Oxidative Stress in Mouse Renal Proximal Tubule Cells

Arany

Faisal

Nagamine

et al. 2008

Journal of Biological Chemistry

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“…Of interest, a recent report indicated that CREB activation also plays a critical role in mediating Erk-1/2-induced tubular epithelial cell survival after oxidant stress. 33 Therefore, it is conceivable that CREB activation may be vital for mediating the beneficial effects of HGF by virtue of its ability to induce SnoN expression and to promote tubular epithelial cell survival. Consistently, attenuation of renal fibrosis and induction of SnoN after administration of HGF gene in vivo are closely correlated with the activation of Erk-1/2 and CREB in obstructive nephropathy ( Figure 9).…”

Section: Hgf Induces Erk-1/2 and Creb Activation In Vivomentioning

confidence: 99%

Molecular Basis for the Cell Type–Specific Induction of SnoN Expression by Hepatocyte Growth Factor

Tan¹,

Zhang²,

Yang³

et al. 2007

Journal of the American Society of Nephrology

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Hepatocyte growth factor (HGF) is a potent antifibrotic cytokine that antagonizes the TGF-␤1/Smad signaling in diverse types of kidney cells by different mechanisms. HGF is shown to induce Smad co-repressor Sloan-Kettering Institute proto-oncogene-related novel gene, non-Alu-containing (SnoN) expression in proximal tubular epithelial cells (HKC-8) but not in glomerular mesangial cells and interstitial fibroblasts. This study investigated the molecular mechanisms underlying the cell type-specific induction of SnoN by HGF. Treatment of HKC-8 cells with actinomycin D completely abolished HGFmediated SnoN induction, suggesting its dependence on gene transcription. Although HGF activated several signal pathways in HKC-8 cells, blockade of extracellular signal-regulated kinase-1 and -2 (Erk-1/2) activation but not Akt and p38 mitogen-activated protein kinase abolished SnoN induction. HGF rapidly activated both upstream and downstream signaling of Erk-1/2, which led to the activation of the cAMP response element-binding protein (CREB). In the promoter region of human SnoN gene, two cAMP response elements were located in close proximity to Sp1 sites. Chromatin immunoprecipitation assay revealed that activated CREB and Sp1 bound to their cognate cis-acting elements in SnoN promoter in response to HGF stimulation. Ectopic expression of wild-type CREB promoted SnoN expression, whereas dominant negative mutant CREB abrogated SnoN induction by HGF. Likewise, chemical blockade of Sp1 binding abolished HGF-mediated SnoN induction. Furthermore, HGF selectively induced CREB phosphorylation in HKC-8 cells but not in mesangial cells and fibroblasts. In vivo, administration of HGF gene induced renal Erk-1/2 phosphorylation, CREB activation, and SnoN expression in obstructive nephropathy. Collectively, these results suggest that CREB activation, in concert with Sp1, constitutes a molecular switch that confers the cell type-specific induction of SnoN in response to HGF stimulation.

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Basal and Src kinase‐mediated activation of the EphA2 promoter requires a cAMP‐responsive element but is CREB‐independent

Baldwin

Hooker

et al. 2011

J of Cellular Biochemistry

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We have previously identified the EphA2 receptor tyrosine kinase as a potentially important injury-responsive gene and a transcriptional target of Src kinase activity in renal ischemia-reperfusion injury (IRI). In the present study, we confirmed, using EphA2 gene trap mice that the endogenous EphA2 promoter is strongly activated following renal IRI. We also examined in more detail the mechanisms responsible for Src kinase-induced activation of the -2 kb human EphA2 promoter and found that the minimal Src-responsive elements were contained in the -145 to +137 region of the human EphA2 gene. This region contains a canonical cAMP-responsive element (CRE) that we found to be critical for both basal and Src kinase-induced transcriptional activity. However, despite activation of the prototypical CRE-binding factor CREB by the Src kinase Fyn, siRNA-mediated knockdown of CREB had no significant impact on either basal or Fyn-induced EphA2 promoter activity. Similarly, activation of CREB by the adenylate cyclase agonist forskolin failed to induce EphA2 promoter activation. Thus, Src kinase-induced activation of the EphA2 promoter is CRE-dependent but CREB-independent.

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CREB mediates ERK-induced survival of mouse renal tubular cells after oxidant stress

Abstract: We show that survival during oxidant stress is mediated through CREB and identification of its downstream targets will reveal important survival pathways.

Cited by 52 publications

References 41 publications

p66 Inhibits Pro-survival Epidermal Growth Factor Receptor/ERK Signaling during Severe Oxidative Stress in Mouse Renal Proximal Tubule Cells

p66 Inhibits Pro-survival Epidermal Growth Factor Receptor/ERK Signaling during Severe Oxidative Stress in Mouse Renal Proximal Tubule Cells

Molecular Basis for the Cell Type–Specific Induction of SnoN Expression by Hepatocyte Growth Factor

Basal and Src kinase‐mediated activation of the EphA2 promoter requires a cAMP‐responsive element but is CREB‐independent

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