PUBLICATION
VBP1 negatively regulates CHIP and selectively inhibits the activity of hypoxia-inducible factor (HIF)-1α but not HIF-2α
- Authors
- Yue, Y., Tang, Y., Huang, H., Zheng, D., Liu, C., Zhang, H., Liu, Y., Li, Y., Sun, X., Lu, L.
- ID
- ZDB-PUB-230519-32
- Date
- 2023
- Source
- The Journal of biological chemistry 299(6): 104829 (Journal)
- Registered Authors
- Liu, Yunzhang, Zhang, Haifeng
- Keywords
- CHIP, HIF-1α, HIF-2α, VBP1, pVHL
- MeSH Terms
-
- Animals
- Carcinoma, Renal Cell*/genetics
- Carcinoma, Renal Cell*/metabolism
- Cytoskeletal Proteins
- Humans
- Hypoxia
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Kidney Neoplasms*/genetics
- Kidney Neoplasms*/metabolism
- Molecular Chaperones
- Transcription Factors/metabolism
- Von Hippel-Lindau Tumor Suppressor Protein/genetics
- Von Hippel-Lindau Tumor Suppressor Protein/metabolism
- Zebrafish/metabolism
- PubMed
- 37201586 Full text @ J. Biol. Chem.
Citation
Yue, Y., Tang, Y., Huang, H., Zheng, D., Liu, C., Zhang, H., Liu, Y., Li, Y., Sun, X., Lu, L. (2023) VBP1 negatively regulates CHIP and selectively inhibits the activity of hypoxia-inducible factor (HIF)-1α but not HIF-2α. The Journal of biological chemistry. 299(6):104829.
Abstract
Hypoxia-inducible factor-1 (HIF-1) is a critical transcription factor that regulates expression of genes involved in cellular adaptation to low oxygen levels. Aberrant regulation of the HIF-1 signaling pathway is linked to various human diseases. Previous studies have established that HIF-1α is rapidly degraded in a von Hippel-Lindau protien (pVHL)-dependent manner under normoxic conditions. In this study, we find that pVHL binding protein 1 (VBP1) is a negative regulator of HIF-1α but not HIF-2α using zebrafish as an in vivo model and in vitro cell culture models. Deletion of vbp1 in zebrafish caused Hif-1α accumulation and upregulation of Hif target genes. Moreover, vbp1 was involved in induction of hematopoietic stem cells (HSCs) under hypoxic conditions. However, VBP1 interacted with and promoted the degradation of HIF-1α in a pVHL-independent manner. Mechanistically, we identify the ubiquitin ligase CHIP and HSP70 as new VBP1 binding partners, and demonstrate that VBP1 negatively regulated CHIP and facilitated CHIP-mediated degradation of HIF-1α. In patients with clear cell renal cell carcinoma (ccRCC), lower VBP1 expression was associated with worse survival outcomes. In conclusion, our results link VBP1 with CHIP stability and provide insights into underlying molecular mechanisms of HIF-1α-driven pathological processes.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping