Endothelium
Neil Herring, David J. Paterson in Levick's Introduction to Cardiovascular Physiology, 2018
What regulates VEGF secretion in such a way as to produce a capillary within 20-50 pm of most cells, and the highest capillary density in the most active tissues? The answer is that a shortage of O2 stimulates cells to produce hypoxia-inducible factor (HIF1), a gene-regulating protein (transcription factor). During normoxia, the a subunit of HIF1 is hydroxylated by HIF prolyl-hydroxylases and targeted for degradation by von Hippel-Lindau tumor suppressor (pVHL) protein. During hypoxia, the HIF1a and β subunits are stabilized. HIF binds to HIF responsive elements (HREs) in a gene promoter to stimulate the transcription of the VEGFA. gene, which in turn leads to angiogenesis. When sufficient new vessels have formed, the O2 supply becomes adequate, so HIF levels fall and VEGF production is switched off. If VEGF production fails to switch off, the result is a haemangioblastoma, a tumour composed largely of a dense mass of blood vessels.
Overview of Angiogenesis: Molecular and Structural Features
Robert J. Gropler, David K. Glover, Albert J. Sinusas, Heinrich Taegtmeyer in Cardiovascular Molecular Imaging, 2007
HIF-1α is degraded under normoxic conditions by a proteosome-dependent pathway, but hypoxia confers stability that enables the protein to accumulate intracellularly. This occurs because the baseline degradation of HIF-1α depends on its post-translational modification, a process that requires oxygen as a cofactor. The Von Hippel-Lindau protein (a member of the ubiquitin ligase family) marks HIF-1α for subsequent degradation only if HIF-1α is post-translationally modified by prolyl hydroxylase-containing enzymes (4). By requiring oxygen (as well as ascorbic acid and iron), prolyl hydroxylase function ultimately results in the modulation of intracellular HIF-1α concentration. Under hypoxic conditions, hydroxylation of HIF-1α is therefore ineffective, the protein becomes less readily degraded, and it subsequently accumulates in the cell.
Vitamin C in Immune Cell Function
Qi Chen, Margreet C.M. Vissers in Vitamin C, 2020
The hypoxia-induced transcription factors are expressed ubiquitously and are heterodimeric complexes of a constitutively expressed β subunit and a regulatory α subunit (isoforms HIF-1α, HIF-2α, HIF-3α). HIF activation is regulated by posttranslational modification of proline and asparagine residues on the HIF-α proteins [59–61,68]. This reaction is carried out by hydroxylases that are members of the 2-OGDD family [18,68,69]. Proline hydroxylation results in recruitment of von Hippel-Lindau protein and targeting to the proteasome for protein degradation. Asparagine modification prevents the formation of an active transcription complex, and the combined hydroxylation events thereby provide a dual control mechanism to prevent inadvertent activation of HIF-mediated transcription [18,68,69]. Three proline hydroxylases, PHD1-3, and the asparagine hydroxylase known as factor inhibiting HIF (FIH) are grouped together as the HIF hydroxylases and represent a distinct subset of 2-OGGDs with unique oxygen sensing capacity [68,69]. These enzymes have been shown to require ascorbate for optimal activity [70,71]. This dependency has been demonstrated in cell free systems [68,71,72], and other reducing agents such as glutathione are much less effective as recyclers of the hydroxylase active site Fe2+ [71,73–76]. Depleted intracellular ascorbate levels have been shown to contribute to the upregulation of HIF activation, particularly under conditions of mild or moderate hypoxia [70,77].
Combination therapies in clinical trials for renal cell carcinoma: how could they impact future treatments?
Published in Expert Opinion on Investigational Drugs, 2021
mccRCC is immunogenic and angiogenic. The von Hippel Lindau tumor suppressor (pVHL) located on Chromosome 3p is an important mediator of angiogenesis; 80% of ccRCCs have a mutation or silencing of pVHL [4]. The product of the pVHL gene forms a stable complex with cellular proteins, and this mediates the cellular response to hypoxia both independently of and via the transcription factor, hypoxia inducible factor (HIF) [5,6]. Downstream targets of HIF have a wide variety of functions including angiogenesis, glucose metabolism, mitogeneis, and cell cycle regulation. In pVHL deficient cell lines, these functions are regulated abnormally and pVHL is unable to mark HIF for proteolytic degradation even in the presence of oxygen [7]. An important pro-angiogenic downstream target of HIF is the vascular endothelial growth factor (VEGF) and its receptor (VEGFR).
Identification of inhibitors targeting HIF-2α/c-Myc by molecular docking and MM-GBSA technology
Published in Journal of Receptors and Signal Transduction, 2021
Lijun Feng, Chuance Sun, Xiaohua Sun, Yang Zhao, Rilei Yu, Congmin Kang
Clear cell renal cell carcinoma (ccRCC) is one of the most dangerous adult malignances in the world, and the cause of ccRCC has become the research focus, recently. Most ccRCCs are associated with inactivation of the von Hippel-Lindau tumor suppressor gene (VHL), and it is also related to the expression of HIF-2α [1]. Hypoxia-inducible factor (HIF) is expressed in organisms and is a basic helix-loop-helix (bHLH) Per-ARNT-Sim (PAS) domain transcription factor. HIF includes HIFα (related protein HIF-1α, HIF-2α, and HIF-3α) and HIFβ (aryl hydrocarbon receptor nuclear translocator) subunits. HIFα and HIFβ formed heterodimers. Heterodimer complexes are involved in transcription and regulate the expression of genes related to hypoxia mechanisms [2]. In the case of sufficient oxygen in the cell, HIFα can be degrades by protease after a series of reactions [3]. However, under the conditions of hypoxia and VHL protein inactivation [4], HIF-α subunits quickly accumulated and entered the nucleus forming a dimer with HIF-1β. This dimer regulates the expression of multiple gene and is a key transcriptional regulator of neoangiogenesis [5–7]. The transcriptional activity of HIF-2α enhances the tumor’s adaptability, growth ability, and metastatic potential [8]. Interestingly, HIF-1α and HIF-2α behave in opposite ways in VHL-deficient RCCs: Overexpression of HIF-2α promotes an increase in the mass of RCC tumors, while increased expression of HIF-1α suppresses the tumor’s growth [9].
Investigational hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) for the treatment of anemia associated with chronic kidney disease
Published in Expert Opinion on Investigational Drugs, 2018
Lucia Del Vecchio, Francesco Locatelli
The HIF system is tightly regulated by a class of O2-sensitive enzymes, the prolyl-hydroxyl domain (PHD). They belong to a family of dioxygenase enzymes that require oxygen, iron, and 2-oxyglutarate (2-OG) for their catalytic activity. In normal O2 conditions, the PHD hydroxylates the HIFα subunit, which in turn binds to the von Hippel-Lindau protein–elongin B/C complex and is then fast degraded by proteasomes [23]. PHD degradation is very effective: in normal oxygen conditions, HIFα half-life is of only 5 min. Conversely, under hypoxic conditions, PHD activity decreases due to the lack of one of its main co-substrate; HIFα can then bind to the HIFβ subunit, translocate into the nucleus, and master the physiological response of the body to hypoxia.
Related Knowledge Centers
- Angiogenesis
- Protein
- Tumor Suppressor Gene
- Ubiquitin Ligase
- Apoptosis
- Renal Cell Carcinoma
- Gene
- Von Hippel–Lindau Disease
- Hypoxia-Inducible Factor
- Transcription Factor