Abstract
Hypoxia-inducible factor 1-alpha (HIF-1α) 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-1α protein. In this pathway, Nkx3.2, a chondrogenic factor, in conjunction with CHIP E3 ligase and p62/SQSTM1 adaptor, induces HIF-1α 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-1α 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.
| Original language | English |
|---|---|
| Pages (from-to) | 127-138 |
| Number of pages | 12 |
| Journal | Cellular Signalling |
| Volume | 36 |
| DOIs | |
| Publication status | Published - 2017 Aug 1 |
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All Science Journal Classification (ASJC) codes
- Cell Biology
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Nkx3.2 induces oxygen concentration-independent and lysosome-dependent degradation of HIF-1α to modulate hypoxic responses in chondrocytes. / Im, Suhjean; Kim, Dae Won.
In: Cellular Signalling, Vol. 36, 01.08.2017, p. 127-138.Research output: Contribution to journal › Article
TY - JOUR
T1 - Nkx3.2 induces oxygen concentration-independent and lysosome-dependent degradation of HIF-1α to modulate hypoxic responses in chondrocytes
AU - Im, Suhjean
AU - Kim, Dae Won
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Hypoxia-inducible factor 1-alpha (HIF-1α) 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-1α protein. In this pathway, Nkx3.2, a chondrogenic factor, in conjunction with CHIP E3 ligase and p62/SQSTM1 adaptor, induces HIF-1α 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-1α 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.
AB - Hypoxia-inducible factor 1-alpha (HIF-1α) 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-1α protein. In this pathway, Nkx3.2, a chondrogenic factor, in conjunction with CHIP E3 ligase and p62/SQSTM1 adaptor, induces HIF-1α 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-1α 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.
UR - http://www.scopus.com/inward/record.url?scp=85019216067&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019216067&partnerID=8YFLogxK
U2 - 10.1016/j.cellsig.2017.05.001
DO - 10.1016/j.cellsig.2017.05.001
M3 - Article
VL - 36
SP - 127
EP - 138
JO - Cellular Signalling
JF - Cellular Signalling
SN - 0898-6568
ER -