Nkx3.2 induces oxygen concentration-independent and lysosome-dependent degradation of HIF-1α to modulate hypoxic responses in chondrocytes

Suhjean Im, Dae Won Kim

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 languageEnglish
Pages (from-to)127-138
Number of pages12
JournalCellular Signalling
Volume36
DOIs
Publication statusPublished - 2017 Aug 1

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Hypoxia-Inducible Factor 1
Chondrocytes
Lysosomes
Cartilage
Oxygen
Ubiquitin-Protein Ligases
Growth Plate
Autophagy
Proteasome Endopeptidase Complex
Metabolic Networks and Pathways
Reporter Genes
Osteogenesis
Skeleton
Proteins
Transcription Factors
Cell Culture Techniques
DNA
Genes

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

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title = "Nkx3.2 induces oxygen concentration-independent and lysosome-dependent degradation of HIF-1α to modulate hypoxic responses in chondrocytes",
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.",
author = "Suhjean Im and Kim, {Dae Won}",
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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

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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.

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