Targeted disruption of
            <i>hsp70.1</i>
            sensitizes to osmotic stress

Shim, Eun Hee; Kim, Jong‐Il; Bang, Eui Suk; Heo, Jun; Lee, Jae Seon; Kim, Eun Young; Lee, Jong Eun; Park, Woong-Yang; Kim, Soon Hee; Kim, Hyung S; Smithies, Oliver; Jang, Ja Joon; Jin, Dong Il; Seo, Jeong Sun

doi:10.1093/embo-reports/kvf175

Cited by 83 publications

(75 citation statements)

References 19 publications

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“…The coordinated induction of these genes is crucial for cell survival (4,46). Because the kidney is the only organ where extreme hyperosmolality is regularly encountered because of the operation of the urine concentration mechanism, it is conceivable that prompt nuclear accumulation of OREBP/TonEBP, as mediated by NLS, is a key step in the timely induction of gene expression to ensure cellular protection.…”

Section: Discussionmentioning

confidence: 99%

“…Hypertonicity also induces the expression of heat shock protein 70 (HSP-70) (3) that acts as a molecular chaperone to protect cells from osmotic stress-induced apoptosis (4). The accumulation of organic osmolytes is brought about by the induction of a battery of genes, including aldose reductase (AR), betaine/␥-aminobutyric acid transporter (BGT-1), and Na ϩ -dependent myoinositol transporter (SMIT), which is responsible for the synthesis of sorbitol and the uptake of betaine and myoinositol, respectively.…”

mentioning

confidence: 99%

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Regulation of Nucleocytoplasmic Trafficking of Transcription Factor OREBP/TonEBP/NFAT5

Tong

Guo

Huang

et al. 2006

Journal of Biological Chemistry

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The osmotic response element-binding protein (OREBP), also known as tonicity enhancer-binding protein (TonEBP) or NFAT5, regulates the hypertonicity-induced expression of a battery of genes crucial for the adaptation of mammalian cells to extracellular hypertonic stress. The activity of OREBP/TonEBP is regulated at multiple levels, including nucleocytoplasmic trafficking. OREBP/TonEBP protein can be detected in both the cytoplasm and nucleus under isotonic conditions, although it accumulates exclusively in the nucleus or cytoplasm when subjected to hypertonic or hypotonic challenges, respectively. Using immunocytochemistry and green fluorescent protein fusions, the protein domains that determine its subcellular localization were identified and characterized. We found that OREBP/TonEBP nuclear import is regulated by a nuclear localization signal. However, under isotonic conditions, nuclear export of OREBP/TonEBP is mediated by a CRM1-dependent, leucine-rich canonical nuclear export sequence (NES) located in the N terminus. Disruption of NES by site-directed mutagenesis yielded a mutant OREBP/TonEBP protein that accumulated in the nucleus under isotonic conditions but remained a target for hypotonicity-induced nuclear export. More importantly, a putative auxiliary export domain distal to the NES was identified. Disruption of the auxiliary export domain alone is sufficient to abolish the nuclear export of OREBP/TonEBP induced by hypotonicity. By using bimolecular fluorescence complementation assay, we showed that CRM1 interacts with OREBP/TonEBP, but not with a mutant protein deficient in NES. Our findings provide insight into how nucleocytoplasmic trafficking of OREBP/TonEBP is regulated by changes in extracellular tonicity.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Regulation of Nucleocytoplasmic Trafficking of Transcription Factor OREBP/TonEBP/NFAT5

Tong

Guo

Huang

et al. 2006

Journal of Biological Chemistry

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“…It has been previously shown that hsp70.1 is responsible for inducing Hsp70 in response to hypertonic stress in mice, and plays a cytoprotective role against the stress Shim et al, 2002). Woo et al reported that the transcriptional activator Tonicity-responsive enhancer (TonE) binding protein (TonEBP) regulates the induction of hsp70.1 in response to hypertonic stress (Woo et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Several reports have suggested the possibility that hypertonic stress and hsp70 induction may be related to the human kidney disease process (Sheikh-Hamad et al, 2001;Shim et al, 2002;Dmitrieva and Burg, 2005). However, the induction of hsp70 by hypertonic stress as well as its protective role in human cell is unclear.…”

Section: Introductionmentioning

confidence: 99%

The role of tonicity responsive enhancer sites in the transcriptional regulation of human hsp70-2 in response to hypertonic stress

Heo

Lee²,

Kim³

et al. 2006

Exp Mol Med

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The inducible 70 kDa heat shock proteins (Hsp70) in mice are encoded by two almost identical genes, hsp70.1 and hsp70.3. Studies have found that only hsp70.1 is induced by hypertonic stress while both hsp70.1 and hsp70.3 genes are expressed in response to heat shock stress. It is unclear if the human counterparts, hsp70-2 and hsp70-1, are differentially regulated by heat shock and osmotic stress. This study found that only hsp70-2 was induced by hypertonic stress in human embryonic kidney epithelial cells and fibroblasts, while heat shock stress induced both hsp70-1 and hsp70-2. The human hsp70-2 promoter region contains three TonE (tonicity-responsive enhancer) sites, which were reported to play an important role in the response to hypertonicity. When the reporter plasmids containing different parts of the 5' flanking region of hsp70-2 were transfected into human embryonic kidney epithelial cells or fibroblasts, one TonE site at -135 was found to play a key role in the response to hypertonicity. The inactivation of the TonE site using site-directed mutagenesis led to the complete loss of induction by hypertonicity, which demonstrates the essential role of the TonE site. This suggests that the TonE site and the TonEBP (TonE binding protein) are the major regulators for the cellular response against high osmolarity in human kidney tissue.

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“…No induction is observed after oxidative stress. [10][11][12] hsp70.1 is constitutively transcribed from one-cell stage to blastocyst stage, 13 whereas hsp70.3 is constitutively expressed from two-cell stage. 14 By the blastocyst stage, the expression of the two genes becomes heat inducible.…”

Section: Introductionmentioning

confidence: 99%

Stress response in mesoangioblast stem cells

Geraci

Turturici

Galli³

et al. 2005

Cell Death Differ

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Stem cells are presumed to survive various stresses, since they are recruited to areas of tissue damage and regeneration, where inflammatory cytokines and cytotoxic cells may result in severe cell injury. We explored the ability of mesoangioblasts to respond to different cell stresses such as heat, heavy metals and osmotic stress, by analyzing heat shock protein (HSP)70 synthesis as a stress indicator. We found that the A6 mesoangioblast stem cells constitutively synthesize HSP70 in a heat shock transcription factor (HSF)-independent way. However, A6 respond to heat shock and cadmium treatment by synthesizing HSP70 over the constitutive expression and this synthesis is HSF1 dependent. The exposure of A6 to copper or to a hypertonic medium does neither induce HSP70 synthesis nor activation of HSF1, while a constitutive binding of constitutive heat shock element binding factor was found. Together, these data suggest that mesoangioblasts constitutively express HSP70 as an 'a priori ' activation mechanism, while they maintain the ability to respond to stress stimuli.

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Targeted disruption of hsp70.1 sensitizes to osmotic stress

Cited by 83 publications

References 19 publications

Regulation of Nucleocytoplasmic Trafficking of Transcription Factor OREBP/TonEBP/NFAT5

Regulation of Nucleocytoplasmic Trafficking of Transcription Factor OREBP/TonEBP/NFAT5

The role of tonicity responsive enhancer sites in the transcriptional regulation of human hsp70-2 in response to hypertonic stress

Stress response in mesoangioblast stem cells

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