Role of the von Hippel-Lindau tumour suppressor protein in the regulation of HIF-1alpha and its oxygen-regulated transactivation domains at high cell density
| Autor: | Ben J Roberts, Steve M Paltoglou |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Transcriptional Activation
Cancer Research medicine.medical_specialty endocrine system diseases Tumor suppressor gene Monosaccharide Transport Proteins Ubiquitin-Protein Ligases Tumour suppressor protein chemistry.chemical_element Cell Count Biology urologic and male genital diseases medicine.disease_cause Response Elements Oxygen Cell Line Transactivation Internal medicine Genetics medicine Humans cardiovascular diseases Von Hippel–Lindau disease neoplasms Molecular Biology Glucose Transporter Type 1 Tumor Suppressor Proteins HIF-1alpha High cell medicine.disease Hypoxia-Inducible Factor 1 alpha Subunit female genital diseases and pregnancy complications Cell biology Endocrinology chemistry Von Hippel-Lindau Tumor Suppressor Protein Carcinogenesis Transcription Factors |
| Zdroj: | Oncogene. 24(23) |
| ISSN: | 0950-9232 |
| Popis: | Hypoxia-inducible factor-1alpha (HIF-1alpha) induction and associated transcription were investigated during high cell density, focusing on the negative regulator of HIF-1alpha expression, the von Hippel-Lindau (VHL) protein. In 293T and HeLa cells, HIF-1alpha protein levels and associated transcription were induced as cells approached confluence. To determine whether these changes were due to a deficit in nuclear VHL-mediated ubiquitination of HIF-1alpha at confluence, cells were stably transfected with VHL. Overexpression of VHL in 293T cells had no demonstrable effect on the induction and nuclear accumulation of HIF-1alpha during high cell density or associated transcription. Moreover, RCC cells stably transfected with full-length VHL failed to exhibit the cell-density-dependent induction of HIF-1alpha noted in other cell lines. Investigation of both N-terminal and C-terminal (aa 727-826) oxygen-regulated proline and asparagine hydroxylation of HIF-1alpha revealed that both are inhibited during high cell density, as determined by impaired capture of HIF-1alpha by VHL and enhanced C-terminal transactivation. Finally, cell-density-mediated induction of HIF-1alpha and GLUT1 in RCC cells could be completely reconstituted by mutations in VHL binding affinity, suggesting that cell-density dependent induction of HIF-1alpha and transactivation may underpin some of the deregulated gene expression observed in VHL disease. |
| Databáze: | OpenAIRE |
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