共查询到20条相似文献,搜索用时 0 毫秒
1.
2.
Histone deacetylase inhibitors induce VHL and ubiquitin-independent proteasomal degradation of hypoxia-inducible factor 1alpha 下载免费PDF全文
Adaptation to hypoxic microenvironment is critical for tumor survival and metastatic spread. Hypoxia-inducible factor 1alpha (HIF-1alpha) plays a key role in this adaptation by stimulating the production of proangiogenic factors and inducing enzymes necessary for anaerobic metabolism. Histone deacetylase inhibitors (HDACIs) produce a marked inhibition of HIF-1alpha expression and are currently in clinical trials partly based on their potent antiangiogenic effects. Although it has been postulated that HDACIs affect HIF-1alpha expression by enhancing its interactions with VHL (von Hippel Lindau), thus promoting its ubiquitination and degradation, the actual mechanisms by which HDACIs decrease HIF-1alpha levels are not clear. Here, we present data indicating that HDACIs induce the proteasomal degradation of HIF-1alpha by a mechanism that is independent of VHL and p53 and does not require the ubiquitin system. This degradation pathway involves the enhanced interaction of HIF-1alpha with HSP70 and is secondary to a disruption of the HSP70/HSP90 axis function that appears mediated by the activity of HDAC-6. 相似文献
3.
4.
5.
6.
The role of mitochondria in the regulation of hypoxia-inducible factor 1 expression during hypoxia 总被引:15,自引:0,他引:15
Agani FH Pichiule P Chavez JC LaManna JC 《The Journal of biological chemistry》2000,275(46):35863-35867
7.
8.
9.
Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1 总被引:1,自引:0,他引:1
Semenza GL 《The Biochemical journal》2007,405(1):1-9
10.
Kubo T Maezawa N Osada M Katsumura S Funae Y Imaoka S 《Biochemical and biophysical research communications》2004,318(4):1006-1011
Bisphenol A (BpA), an endocrine-disrupting chemical, is known to be a xenoestrogen and to affect the reproductive functions of animals. Recent reports have documented BpA-induced developmental abnormalities in the neuronal systems of humans and animals, and these effects appear to be non-estrogenic. In this study, we found that BpA inhibited the hypoxic response of human hepatoma cells. The expression of hypoxic response genes such as the erythropoietin (EPO) gene is done via a hypoxia inducible factor 1 (HIF-1)-dependent signaling pathway. To investigate possible structural requirements for this inhibitory effect, several BpA analogs were synthesized and added to this system. The blocking of two phenol groups in BpA did not change the effect, but the inhibition completely disappeared by the removal of two central methyl groups in BpA (the resulting compound is designated BpF). BpA, but not BpF, promoted degradation of the HIF-1alpha protein, which is a component of HIF-1, followed by inhibition of EPO induction. An immunoprecipitation assay indicated that BpA dissociated heat shock protein 90 (Hsp90) from HIF-1alpha and destabilized HIF-1alpha protein. HIF-1alpha is usually degraded first by ubiquitination and then by the proteasome pathway. Cobalt ion inhibits ubiquitination of HIF-1alpha and stabilizes it. In the present study, BpA promoted HIF-1alpha degradation in the presence of cobalt and in the presence of proteasome inhibitor. These results suggest that BpA degraded HIF-1alpha via a currently unknown pathway, and that this phenomenon required two methyl groups in BpA. 相似文献
11.
12.
Zhou B Ann DK Li X Kim KJ Lin H Minoo P Crandall ED Borok Z 《American journal of physiology. Cell physiology》2007,292(4):C1280-C1290
13.
14.
15.
16.
17.
18.
19.
Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway 总被引:40,自引:0,他引:40
Kallio PJ Wilson WJ O'Brien S Makino Y Poellinger L 《The Journal of biological chemistry》1999,274(10):6519-6525