ATM, a DNA damage-inducible kinase, contributes to activation by high NaCl of the transcription factor TonEBP/OREBP

Irarrázabal, Carlos E.; Liu, Jennifer C.; Burg, Maurice B.; Ferraris, Joan D.

doi:10.1073/pnas.0403062101

Cited by 106 publications

(184 citation statements)

References 26 publications

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“…Hyperosmotic stress enhances translocation of NFAT5 into the nucleus through phosphorylation by signal molecules, such as ATM, Fyn, p38, and protein kinase A (32)(33)(34). In this study, we demonstrated, for the first time, that NFAT5 activity was regulated through the proteasome-mediated proteolysis pathway under cytotoxic conditions, proposing a novel regulatory mechanism of NFAT5 activity.…”

Section: Discussionmentioning

confidence: 69%

“…Taken together, it is likely that Dox-induced degradation of NFAT5 is mediated by a proteasome-mediated proteolytic process in an ubiquitinindependent manner. NFAT5 activity is regulated by some protein kinases (32)(33)(34). NFAT5 is phosphorylated under hypertonic condition, and NFAT5 phosphorylation is shown to be a critical event for nuclear translocation, followed by DNA binding (41,42).…”

Section: Discussionmentioning

confidence: 99%

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Degradation of NFAT5, a Transcriptional Regulator of Osmotic Stress-related Genes, Is a Critical Event for Doxorubicin-induced Cytotoxicity in Cardiac Myocytes

Ito

Fujio

Takahashi

et al. 2007

Journal of Biological Chemistry

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Nuclear factor-activated T cell 5 (NFAT5), a novel member of the NFAT family of proteins, was originally identified as a transcriptional factor responsible for adaptation to hyperosmotic stress. Though NFAT5 is ubiquitously expressed, the biological functions of NFAT5 remain to be clarified, especially in the tissues that are not exposed to hypertonicity, including hearts. In the present study, we focused on the cardioprotective roles of NFAT5 against the cardiotoxic anti-tumor agent doxorubicin (Dox). In cultured cardiomyocytes, transcripts of the hypertonicity-inducible genes, such as taurine transporter (TauT) and sodium/myo-inositol transporter, were down-regulated by Dox. Interestingly, NFAT5 protein, but not mRNA, was decreased in cardiomyocytes exposed to Dox. Treatment of proteasome inhibitors, MG-132 or proteasome-specific inhibitor 1, prevented the Dox-mediated decrease of NFAT5 protein. Further, ubiquitin-conjugated NFAT5 was not detected in cultured cardiomyocytes treated with MG-132 and/or Dox, as assessed by immunoprecipitation assay, suggesting Dox-induced degradation through ubiquitin-independent proteasome pathway. Importantly, inhibition of NFAT5 with overexpression of dominant-negative NFAT5 decreased cell viability and increased creatine kinase leakage into culture medium. Consistently, small interfering RNA targeting NFAT5 gene enhanced myocyte death. These findings suggest that Dox promoted the degradation of NFAT5 protein, reducing cell viability in cardiomyocytes. This is the first demonstration that NFAT5 is a positive regulator of cardiomyocyte survival.Because mature cardiac myocytes have a limited proliferative potential, accumulation of cardiomyocyte death leads to heart failure. Pathologically, cardiac myocyte death is induced by various kinds of stresses, such as hypoxia, mechanical stress, and cardiotoxic drugs. Among them, doxorubicin (Dox), 2 an antitumor agent of the anthracycline family, is well known to have a harmful effect and its use is limited by irreversible cardiotoxicity (1, 2). Although the precise mechanisms of its myocardial damage are unclear, numerous evidence suggests that Dox induces cardiotoxicity through multiple pathways, including production of reactive oxygen species, perturbation of calcium handling, and selective inhibition of cardiac muscle-specific gene expression (1,3,4). Recently, several reports indicate that Dox activates proteasome-mediated proteolysis that results in the disorder of cardiac gene expression (5, 6).NFAT5 (nuclear factor-activated T cell 5)/TonEBP (tonicityresponse element-binding protein), a member of the rel/NF B/ NFAT family of transcription factors, was originally identified as a transcriptional factor involved in the cellular responses to hypertonic stress (7, 8). Whereas NFAT 1-4 are activated by Ca 2ϩ /calcineurin pathway, NFAT5 activity is regulated in a calcineurin-independent manner, because it lacks the N-terminal NFAT homology region containing the calcineurin regulatory motif (7,8). NFAT5 is activated by phosphorylation ...

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Degradation of NFAT5, a Transcriptional Regulator of Osmotic Stress-related Genes, Is a Critical Event for Doxorubicin-induced Cytotoxicity in Cardiac Myocytes

Ito

Fujio

Takahashi

et al. 2007

Journal of Biological Chemistry

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“…The cellular event involving active p53 is to stimulate the apoptotic infrastructure by increasing the expression of apoptotic protease-activating factor 1 (APAF-1), a crucial component of the apoptosome (Kinzler and Vogelstein, 1997;Levine, 1997). Functional proteins downstream from the p53 interactive signaling pathways, such as ataxia telangiectasia mutated (ATM) and homolog of ATM (ATR), are central to the DNA damage response (Zhou and Elledge, 2000;Goodarzi et al, 2003;Dodson et al, 2004;Irarrazabal et al, 2004;Kastan, 2004;Yang et al, 2004). Further downstream targets (substrates) of ATM/ATR include the checkpoint protein kinases Chk1 and Chk2 (Ma et al, 1998;Matsuoka et al, 1998;Sanchez et al, 1999;Tominaga et al, 1999).…”

Section: Role Of P53 In Uv Irradiation-induced Dna Damagementioning

confidence: 99%

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

2006

Progress in Retinal and Eye Research

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One of the functional roles of the corneal epithelial layer is to protect the cornea, lens and other underlying ocular structures from damages caused by environmental insults. It is important for corneal epithelial cells to maintain this function by undergoing continuous renewal through a dynamic process of wound healing. Previous studies in corneal epithelial cells have provided substantial evidence showing that environmental insults, such as ultraviolet (UV) irradiation and other biohazards, can induce stress-related cellular responses resulting in apoptosis and thus interrupt the dynamic process of wound healing. We found that UV irradiation-induced apoptotic effects in corneal epithelial cells are started by the hyperactivation of K + channels in the cell membrane resulting in a fast loss of intracellular K + ions. Recent studies provide further evidence indicating that these complex responses in corneal epithelial cells are resulted from the activation of stressrelated signaling pathways mediated by K + channel activity. The effect of UV irradiation on corneal epithelial cell fate shares common signaling mechanisms involving the activation of intracellular responses that are often activated by the stimulation of various cytokines. One piece of evidence for making this distinction is that at early times UV irradiation activates a Kv3.4 channel in corneal epithelial cells to elicit activation of c-Jun N-terminal kinase cascades and p53 activation leading to cell cycle arrest and apoptosis. The hypothetic model is that UV-induced potassium channel hyperactivity as an early event initiates fast cell shrinkages due to the loss of intracellular potassium, resulting in the activation of scaffolding protein kinases and cytoskeleton reorganizations. This review article presents important control mechanisms that determine Kv channel activity-mediated cellular responses in corneal epithelial cells, involving activation of stress-induced signaling pathways, arrests of cell cycle progression and/or induction of apoptosis.

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“…Also, hypertonicity increases transactivation activity of TonEBP͞OREBP, associated with phosphorylation of the C-terminal region containing its transactivation domain (4). Several protein kinases are known to contribute to a hypertonicity-induced increase of TonEBP͞ OREBP transcriptional activity and transactivation, including p38 (5,6), Fyn (5), Ataxia telangiectasia mutated (ATM) (7), and protein kinase A (PKAc) (8), none of them, alone, being sufficient for full activation.…”

mentioning

confidence: 99%

“…High NaCl causes DNA doublestrand breaks (10,11) and, like IR, activates ATM by phosphorylation of S1981 (7). This activation of ATM is necessary for full high NaCl-induced TonEBP͞OREBP transcriptional activity (7).…”

mentioning

confidence: 99%

Phosphatidylinositol 3-kinase mediates activation of ATM by high NaCl and by ionizing radiation: Role in osmoprotective transcriptional regulation

Irarrázabal

Burg

Ward

et al. 2006

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

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High NaCl causes DNA double-strand breaks and activates the transcription factor, TonEBP͞OREBP, resulting in increased transcription of several protective genes, including those involved in accumulation of compatible organic osmolytes. Several kinases are known to contribute to signaling activation of TonEBP͞OREBP, including ATM, which is a member of the phosphatidylinositol 3-kinase (PI3K)-like kinase family and is activated by DNA doublestrand breaks. The purpose of the present studies was to investigate a possible role of PI3K Class IA (PI3K-IA). We found that high NaCl increases PI3K-IA lipid kinase activity. Inhibiting PI3K-IA either by expressing a dominant negative of its regulatory subunit, p85, or by small interfering RNA-mediated knockdown of its catalytic subunit, p110␣, reduces high NaCl-induced increases in TonEBP͞ OREBP transcriptional activity and transactivation, but not nuclear translocation of TonEBP͞OREBP, or increases in its abundance. Further, suppression of PI3K-IA inhibits the activation of ATM that is caused by either ionizing radiation or high NaCl. High NaClinduced increase in TonEBP͞OREBP activity is reduced equally by inhibition of ATM or PI3K-IA, and the effects are not additive. The conclusions are as follows: (i) PI3K-IA activity is necessary for both high NaCl-and ionizing radiation-induced activation of ATM and (ii) high NaCl activates PI3K-IA, which, in turn, contributes to full activation of TonEBP͞OREBP via ATM.DNA damage ͉ osmotic stress ͉ TonEBP͞OREBP

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ATM, a DNA damage-inducible kinase, contributes to activation by high NaCl of the transcription factor TonEBP/OREBP

Cited by 106 publications

References 26 publications

Degradation of NFAT5, a Transcriptional Regulator of Osmotic Stress-related Genes, Is a Critical Event for Doxorubicin-induced Cytotoxicity in Cardiac Myocytes

Degradation of NFAT5, a Transcriptional Regulator of Osmotic Stress-related Genes, Is a Critical Event for Doxorubicin-induced Cytotoxicity in Cardiac Myocytes

Stress-induced corneal epithelial apoptosis mediated by K+ channel activation

Phosphatidylinositol 3-kinase mediates activation of ATM by high NaCl and by ionizing radiation: Role in osmoprotective transcriptional regulation

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