Abstract |
The regulation of hypoxia-inducible factor-1α (HIF-1α) during endochondral bone formation is not fully understood. Here, we investigated the cross-talk between HIF-1α and Runt-related transcription factor 2 (Runx2) in the growth plate. Runx2 caused the accumulation of HIF-1α protein in ATDC5 chondrocytes and HEK293 cells under normoxic conditions. Runx2 also increased the nuclear translocation of HIF-1α when coexpressed in HEK293 cells and interacted with HIF-1α at the oxygen-dependent degradation domain ( ODDD). In addition, Runx2 competed with von Hippel-Lindau tumor suppressor protein by directly binding to ODDD-HIF-1α and significantly inhibited the ubiquitination of HIF-1α, even though Runx2 did not change the hydroxylation status of HIF-1α. Furthermore, overexpression of Runx2 resulted in the significant enhancement of vascular endothelial growth factor ( VEGF) promoter reporter activity and protein secretion. Runx2 significantly increased angiogenic activity in human umbilical vein endothelial cells in vitro. In wild-type mice, HIF-1α and Runx2 were colocalized in hypertrophic chondrocytes in which the cluster of differentiation 31 (CD31) protein was expressed at embryonic day 15.5 (E15.5). In contrast, the expression of HIF-1α was markedly reduced in areas of CD31 expression in Runx2(-/-) mice. These results suggest that Runx2 stabilizes HIF-1α by binding to ODDD to block the interaction between von Hippel-Lindau protein and HIF-1α. In conclusion, Runx2, HIF-1α, and VEGF may regulate vascular angiogenesis spatially and temporally in the hypertrophic zone of the growth plate during endochondral bone formation.
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Authors | Sun-Hee Lee, Xiangguo Che, Jae-Hwan Jeong, Je-Yong Choi, Young-Joo Lee, Yong-Hee Lee, Suk-Chul Bae, You-Mie Lee |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 287
Issue 18
Pg. 14760-71
(Apr 27 2012)
ISSN: 1083-351X [Electronic] United States |
PMID | 22351759
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Core Binding Factor Alpha 1 Subunit
- HIF1A protein, human
- Hif1a protein, mouse
- Hypoxia-Inducible Factor 1, alpha Subunit
- RUNX2 protein, human
- Runx2 protein, mouse
- VEGFA protein, human
- Vascular Endothelial Growth Factor A
- vascular endothelial growth factor A, mouse
- Von Hippel-Lindau Tumor Suppressor Protein
- VHL protein, human
- VHL protein, mouse
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Topics |
- Active Transport, Cell Nucleus
(physiology)
- Animals
- Cell Nucleus
(genetics, metabolism)
- Chondrocytes
(cytology, metabolism)
- Core Binding Factor Alpha 1 Subunit
(genetics, metabolism)
- HEK293 Cells
- Humans
- Hydroxylation
(physiology)
- Hypoxia-Inducible Factor 1, alpha Subunit
(genetics, metabolism)
- Mice
- Mice, Knockout
- Neovascularization, Physiologic
- Protein Binding
- Protein Stability
- Protein Structure, Tertiary
- Vascular Endothelial Growth Factor A
(biosynthesis, genetics)
- Von Hippel-Lindau Tumor Suppressor Protein
(genetics, metabolism, physiology)
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