| First Author | Im S | Year | 2017 |
| Journal | Cell Signal | Volume | 36 |
| Pages | 127-138 | PubMed ID | 28479297 |
| Mgi Jnum | J:317647 | Mgi Id | MGI:6856222 |
| Doi | 10.1016/j.cellsig.2017.05.001 | Citation | Im S, et al. (2017) Nkx3.2 induces oxygen concentration-independent and lysosome-dependent degradation of HIF-1alpha to modulate hypoxic responses in chondrocytes. Cell Signal 36:127-138 |
| abstractText | Hypoxia-inducible factor 1-alpha (HIF-1alpha) is a DNA-binding transcription factor regulating hypoxic responses. It plays a key role in vascularization and angiogenesis as well as various metabolic pathways. Interestingly, during early phase endochondral ossification when HIF expression in chondrocytes is evident, developing cartilage primordia remains avascular until hypertrophic calcification commences. In this work, we uncovered a novel pathway causing oxygen concentration-independent and proteasome-independent degradation of HIF-1alpha protein. In this pathway, Nkx3.2, a chondrogenic factor, in conjunction with CHIP E3 ligase and p62/SQSTM1 adaptor, induces HIF-1alpha degradation via a macroautophagy pathway in a hypoxic environment. Consistent with these findings, Nkx3.2 was capable of suppressing HIF-dependent reporter gene activity as well as endogenous HIF target genes in in vitro cell culture. Furthermore, we observed that cartilage-specific Nkx3.2 overexpression in mice attenuates HIF-1alpha protein levels as well as vascularization in cartilage growth plates. Therefore, these results suggest that Nkx3.2-mediated HIF regulation may allow cartilage-specific avascularity under hypoxic conditions during endochondral skeleton development. |
