Exp Mol Med.  2006 Jun;38(3):295-301.

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

  • 1Department of Biochemistry, Hallym University College of Medicine, Chuncheon 200-702, Korea. jongil@hallym.ac.kr
  • 2ILCHUN Molecular Medicine Institute, Seoul National University College of Medicine, Seoul 110-799, Korea.
  • 3Laboratory of Functional Genomics, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.
  • 4Department of Biochemistry and Molecular Biology, Kangwon National University College of Medicine, Chuncheon 200-701, Korea.


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.


HSP70 heat-shock proteins; heat-shock proteins; stress; transcription factors; gene expression regulation

MeSH Terms

Transcription, Genetic/drug effects/genetics
Transcription Factors/genetics/*physiology
Saline Solution, Hypertonic/*pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Protein Binding
Promoter Regions (Genetics)/genetics
Point Mutation
Mutagenesis, Site-Directed
HSP70 Heat-Shock Proteins/*genetics/metabolism
Gene Expression Regulation/*drug effects
DNA-Binding Proteins/genetics/metabolism
Cell Line
Binding Sites/genetics
Base Sequence
5' Flanking Region/genetics
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