Abstract 4373: JNK1 participates in the VHL-independent HIF-1α degradation pathway by regulating Hsp90/Hsp70 turnover and the HDAC6-dependent chaperone activity
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Abstract Nickel has been proved to be a human carcinogen. Hypoxia induced factor-1α (HIF-1α) plays a key role in the pathological processes of cancers. Previous studies have shown that nickel can exert its carcinogenic effects through the induction of HIF-1α accumulation. However, the molecular mechanisms have not been well understood. The c-Jun N-terminal kinase 1 (JNK1) is implicated in several physiological processes, including proliferation, apoptosis and differentiation, which are thought to be involved in several cancer development. JNK1 is also known to regulate the level of Hsp90/Hsp70. Our present study was conducted to investigate the role of JNK1 in the accumulation of HIF-1α induced by nickel. In current studies, we demonstrated that JNK1 is required for such an Hsp-dependent HIF-1α regulation. HIF-1α stabilization was impaired in JNK1−/− cells, and could be rescued by reconstitutional expression of JNK1 in either hypoxia or chemical-mimicked hypoxia conditions. Accordingly, HIF-1-dependent transcriptional activity and its downstream gene's expression were dramatically reduced in JNK1-deficient cells. We further disclosed that in JNK1−/− cells the low expression level of Hsp90/Hsp70 proteins affected the protective roles of these chaperones in maintaining newly synthesized HIF-1α stabilization, and forced expression of Hsp90 or Hsp70 in JNK1−/− cells showed a notable increase in HIF-1α stability compared with that of parental cells. Furthermore, our studies found that defective HDAC6 expression and subsequently increased Hsp90 acetylation could account for the reduction of Hsp90 chaperon activity in JNK1−/− cells. Our studies for the first time disclose a novel function of JNK1 in the modulation of HIF-1ααstabilization under nickel mimicked chemical hypoxia conditions through regulation of Hsp90/Hsp70 expression as well as HDAC6-mediated Hsp90 acetylation modification. This novel function may contribute to JNK1-mediated carcinogenic effects in response to nickel exposure. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4373.Keywords:
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Chaperone (clinical)
Hypoxia
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HSP60
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CADMIUM EXPOSURE
Stressor
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Heat shock proteins(HSPs)are ubiquitous in organisms,with high conservative in organic evolution and expression in physiological condition or stress response.HSP27 which correlated with increasing cell survival in stress response is significant one of the HSPs family.It has been shown that HSP27 regulates apoptosis to prevent cell death by interacting with a large number of important proteins in apoptotic signal pathway.
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OBJECTIVE: To investigate the effects of quercetin on heat shock protein expression in human breast cancer cell MCF-7.METHODS: MCF-7 cells were incubated at 42 ℃ for 2 h in vitro.The changes of gene expression and protein levels of HSP70,HSP27 and HSP90 were detected by real-time PCR and Western-blot after 4,8,12 and 24 hours.MCF-7 cells were pretreated with 150 μmol/L Quercetin before heat treatment,then detected the changes of gene expression and protein levels of HSP70,HSP27 and HSP90.RESULTS: The gene expression and protein levels of HSP70,HSP27 and HSP90 reached to its peak at 4 h,decresed at 8 h and returned to normal level at 24 h after heat treatment.Quercetin could inhibit gene expression and protein levels of HSP70 and HSP27,but up-regulated and delayed descent of HSP90.The level stay in peak at 4 to 8 h and then decrease to normal.CONCLUSIONS: The gene expression and protein levels of HSP70,HSP27 and HSP90 up-regulate quickly after heat treatment.Using quercetin before heat treatment can inhibit gene expression and protein levels of HSP70 and HSP27,but increase and delay that of HSP90.
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Dilated Cardiomyopathy
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HSP27 is an important member of small molecular weight heat shock protein(HSP) family,the external stimulation of free radicals,heat,ischemic and toxic substances can induce the generation of HSP27 in the cell,presenting high expression in a variety of tumors and normal tissues,with especially high expression in cardiac tissue,which have a positive effect in the anti-apoptosis,anti-ischemia injury and anti-inflammatory.It has a regulatory role in the vascular smooth muscle cell proliferation and migration and the occurrence and development of atherosclerosis.HSP27 may be a new therapeutic strategy of cardiovascular diseases.
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Heat shock protein 27 (HSP27) is an important member of small molecular weight heat shock protein family,upregulation when the body under stress,can protect cell function via the effect of molecular chaperone,regulating cell movement,anti apoptosis,anti-oxidative stress and anti-inflammatory.HSP27 is a recently reported potential biomarker of atherosclerosis.The serum HSP27 levels were inversely related to atherosclerotic burden.HSP27 may be a significant new therapeutic target in Atherosclerosis.
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As an important kind of nonspecific cytoprotective proteins,heat shock proteins(HSPs) play a vital role in the stress tolerance and stress protection of immune cells,acting as molecular chaperones or anti-apoptosis effects in the maintenance of the immune cells survival and the stability of the internal environment.HSP70 and HSP27 of small heat shock proteins(sHPSs),an important member of HSPs,have been proved to have significant effect on mediating the cell proliferation,differentiation and apoptosis process.In this paper,the protective effect of HSP70/HSP27 on immune cells under the condition of heat stress was reviewed.
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