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  • Title: HIF-1α and HIF-2α degradation is differentially regulated in nucleus pulposus cells of the intervertebral disc.
    Author: Fujita N, Chiba K, Shapiro IM, Risbud MV.
    Journal: J Bone Miner Res; 2012 Feb; 27(2):401-12. PubMed ID: 21987385.
    Abstract:
    Studies of many cell types show that levels of hypoxia inducible factor (HIF)-1α and HIF-2α are primarily controlled by oxygen-dependent proteasomal degradation, catalyzed by HIF prolyl-hydroxylases (PHDs). However, in the hypoxic niche of the intervertebral disc, the mechanism of HIF-α turnover in nucleus pulposus cells is not yet known. We show that in nucleus pulposus cells HIF-1α and HIF-2α, degradation was mediated through 26S proteasome irrespective of oxygen tension. It is noteworthy that HIF-2α degradation through 26S proteasome was more pronounced in hypoxia. Surprisingly, treatment with DMOG, a PHD inhibitor, shows the accumulation of only HIF-1α and induction in activity of its target genes, but not of HIF-2α. Loss and gain of function analyses using lentiviral knockdown of PHDs and overexpression of individual PHDs show that in nucleus pulposus cells only PHD2 played a limited role in HIF-1α degradation; again HIF-2α degradation was unaffected. We also show that the treatment with inhibitors of lysosomal proteolysis results in a strong accumulation of HIF-1α and to a much smaller extent of HIF-2α levels. It is thus evident that in addition to PHD2 catalyzed degradation, the HIF-1α turnover in nucleus pulposus cells is primarily regulated by oxygen-independent pathways. Importantly, our data clearly suggests that proteasomal degradation of HIF-2α is not mediated by a classical oxygen-dependent PHD pathway. These results for the first time provide a rationale for the normoxic stabilization as well as the maintenance of steady-state levels of HIF-1α and HIF-2α in nucleus pulposus cells.
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