RRC ID 52209
Author Im S, Kim DW.
Title Nkx3.2 induces oxygen concentration-independent and lysosome-dependent degradation of HIF-1α to modulate hypoxic responses in chondrocytes.
Journal Cell Signal
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.
Volume 36
Pages 127-138
Published 2017-8-1
DOI 10.1016/j.cellsig.2017.05.001
PII S0898-6568(17)30130-4
PMID 28479297
MeSH Animals Autophagy / drug effects Cell Hypoxia / drug effects Chondrocytes / cytology* Chondrocytes / drug effects Chondrocytes / metabolism* Homeodomain Proteins / chemistry Homeodomain Proteins / metabolism* Humans Hydroxylation Hypoxia-Inducible Factor 1, alpha Subunit / metabolism* Lysosomes / drug effects Lysosomes / metabolism* Mice, Transgenic Oxygen / pharmacology* Proline / metabolism Protein Binding / drug effects Protein Stability / drug effects Proteolysis* / drug effects Sequestosome-1 Protein / metabolism Transcription Factors / chemistry Transcription Factors / metabolism* Transcription, Genetic / drug effects
IF 3.968
Times Cited 4
Human and Animal Cells ATDC5(RCB0565)