A yeast three-hybrid system that reconstitutes mammalian hypoxia inducible factor regulatory machinery
2008
Background
Several human pathologies, including neoplasia and ischemic cardiovascular diseases, course with an unbalance between oxygen supply and demand (hypoxia). Cells within hypoxic regions respond with the induction of a specific genetic program, under the control of the Hypoxia Inducible Factor (HIF), that mediates their adaptation to the lack of oxygen. The activity of HIF is mainly regulated by the EGL-nine homolog (EGLN) enzymes that hydroxylate the alpha subunit of this transcription factor in an oxygen-dependent reaction. Hydroxylated HIF is then recognized and ubiquitinilated by the product of the tumor suppressor gene, pVHL, leading to its proteosomal degradation. Under hypoxia, the hydroxylation of HIF by the EGLNs is compromised due to the lack of oxygen, which is a reaction cosubstrate. Thus, HIF escapes degradation and drives the transcription of its target genes. Since the progression of the aforementioned pathologies might be influenced by activation of HIF-target genes, development of small molecules with the ability to interfere with the HIF-regulatory machinery is of great interest.
Keywords:
- Transcription factor
- Biology
- Cell biology
- G alpha subunit
- Regulation of gene expression
- Procollagen-proline dioxygenase
- Molecular biology
- Hypoxia-Inducible Factor-Proline Dioxygenases
- Hypoxia-inducible factors
- Hypoxia-Inducible Factor 1
- Tumor suppressor gene
- Hydroxylation
- Gene
- Transcription (biology)
- Biochemistry
- Enzyme
- Correction
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- Cite
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