ArticleJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research2012
Tonicity enhancer binding protein (TonEBP) and hypoxia-inducible factor (HIF) coordinate heat shock protein 70 (Hsp70) expression in hypoxic nucleus pulposus cells: role of Hsp70 in HIF-1α degradation.
Article in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 49 citations in OpenAlex.
- Review
- Heat acclimation mediates cellular protection via HSP70 stabilization of HIF-1α protein in extreme environments.International journal of biological sciences · 2025Article
- Prospects for nasal delivery of a pharmacologic agent for neuroprotective experimental therapy after prenatal hypoxia.Frontiers in systems neuroscience · 2025Article
- Oxygen-controllable injectable hydrogel alleviates intervertebral disc degeneration by balancing extracellular matrix metabolism.Materials today. Bio · 2024Article
- Getting to the Core: Exploring the Embryonic Development from Notochord to Nucleus Pulposus.Journal of developmental biology · 2024Review
- Review
- HSP70 attenuates compression-induced apoptosis of nucleus pulposus cells by suppressing mitochondrial fission via upregulating the expression of SIRT3.Experimental & molecular medicine · 2022Article
- Mitochondrial quality control in intervertebral disc degeneration.Experimental & molecular medicine · 2021Review
- The role of HIF proteins in maintaining the metabolic health of the intervertebral disc.Nature reviews. Rheumatology · 2021Review
- Article
- TonEBP-deficiency accelerates intervertebral disc degeneration underscored by matrix remodeling, cytoskeletal rearrangements, and changes in proinflammatory gene expression.Matrix biology : journal of the International Society for Matrix Biology · 2020Article
- Nucleus pulposus primary cilia alter their length in response to changes in extracellular osmolarity but do not control TonEBP-mediated osmoregulation.Scientific reports · 2019Article
- NFAT5 and HIF-1α Coordinate to Regulate NKCC1 Expression in Hippocampal Neurons After Hypoxia-Ischemia.Frontiers in cell and developmental biology · 2019Article
- COX-2 expression mediated by calcium-TonEBP signaling axis under hyperosmotic conditions serves osmoprotective function in nucleus pulposus cells.The Journal of biological chemistry · 2018Article
- Bicarbonate Recycling by HIF-1-Dependent Carbonic Anhydrase Isoforms 9 and 12 Is Critical in Maintaining Intracellular pH and Viability of Nucleus Pulposus Cells.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2018Article
- Lack of evidence for involvement of TonEBP and hyperosmotic stimulus in induction of autophagy in the nucleus pulposus.Scientific reports · 2017Article
- The novel hypoxia-inducible factor-1α inhibitor IDF-11774 regulates cancer metabolism, thereby suppressing tumor growth.Cell death & disease · 2017Article
- [Protective effects of heat shock protein 70 against hypoxic pulmonary hypertension in neonatal rats].Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics · 2017Article
- Extracellular HSP70-peptide complexes promote the proliferation of hepatocellular carcinoma cells via TLR2/4/JNK1/2MAPK pathway.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Article
- Class I and IIa HDACs Mediate HIF-1α Stability Through PHD2-Dependent Mechanism, While HDAC6, a Class IIb Member, Promotes HIF-1α Transcriptional Activity in Nucleus Pulposus Cells of the Intervertebral Disc.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2016Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The objective of our study was to examine the regulation of hypoxic expression of heat shock protein 70 (Hsp70) in nucleus pulposus cells and to determine if Hsp70 promoted hypoxia-inducible factor (HIF)-1α degradation. Rat nucleus pulposus cells were maintained in culture in either 21% or 1% oxygen. To determine the regulation of Hsp70 expression by tonicity enhancer binding protein (TonEBP) and HIF-1/2, loss-of-function and gain-of-function experiments and mutational analysis of the Hsp70 promoter were performed. Hypoxia increased Hsp70 expression in nucleus pulposus cells. Noteworthy, hypoxia increased TonEBP transactivation and mutation of TonE motifs blocked hypoxic induction of the Hsp70 promoter. In contrast, mutation of hypoxia response element (HRE) motifs coupled with loss-of-function experiments suggested that HIF-1 and HIF-2 suppressed Hsp70 promoter activity and transcription. Interestingly, HIF-α interferes with TonEBP function and suppresses the inductive effect of TonEBP on the Hsp70 promoter. In terms of Hsp70 function, when treated with Hsp70 transcriptional inhibitor, KNK437, there was an increase in HIF-1α protein stability and transcriptional activity. Likewise, when Hsp70 was overexpressed, the stability of HIF-1α and its transcriptional activity decreased. Hsp70 interacted with HIF-1α under hypoxic conditions and evidenced increased binding when treated with MG132, a proteasomal inhibitor. These results suggest that Hsp70 may promote HIF-1α degradation through the proteasomal pathway in nucleus pulposus cells. In hypoxic and hyperosmolar nucleus pulposus cells, Hsp70, TonEBP, and HIFs form a regulatory loop. We propose that the positive regulation by TonEBP and negative regulation of Hsp70 by HIF-1 and HIF-2 may serve to maintain Hsp70 levels in these cells, whereas Hsp70 may function in controlling HIF-1α homeostasis.
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