{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T14:02:07Z","timestamp":1788444127734,"version":"build-2803163510"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2012,2,9]],"date-time":"2012-02-09T00:00:00Z","timestamp":1328745600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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)-1\u03b1 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-\u03b1 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-1\u03b1 protein stability and transcriptional activity. Likewise, when Hsp70 was overexpressed, the stability of HIF-1\u03b1 and its transcriptional activity decreased. Hsp70 interacted with HIF-1\u03b1 under hypoxic conditions and evidenced increased binding when treated with MG132, a proteasomal inhibitor. These results suggest that Hsp70 may promote HIF-1\u03b1 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-1\u03b1 homeostasis. \u00a9 2012 American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbmr.1571","type":"journal-article","created":{"date-parts":[[2012,2,9]],"date-time":"2012-02-09T20:01:46Z","timestamp":1328817706000},"page":"1106-1117","source":"Crossref","is-referenced-by-count":45,"title":["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-1\u03b1 degradation"],"prefix":"10.1093","volume":"27","author":[{"given":"Shilpa S","family":"Gogate","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery and Graduate Program in Cell and Developmental Biology, Jefferson Medical College, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery and Graduate Program in Cell and Developmental Biology, Jefferson Medical College, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata","family":"Skubutyte","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery and Graduate Program in Cell and Developmental Biology, Jefferson Medical College, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irving M","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery and Graduate Program in Cell and Developmental Biology, Jefferson Medical College, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makarand V","family":"Risbud","sequence":"additional","affiliation":[{"name":"Department 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