Regulation and function of human hypoxia-inducible factor-3alpha splice isoforms
Bibliographic record
Abstract
Hypoxia-inducible factors (HIFs) are the heterodimeric transcription factors that mediate the adaptation of a cell, tissue and organism to reduced oxygen availability (hypoxia). HIFs transcriptionally activate genes involved in erythropoiesis, angiogenesis, vascular tone and permeability, glucose metabolism and uptake, cellular motility and invasion, growth, survival, proliferation, differentiation and apoptosis. HIFs are composed of an oxygen-labile a subunit and alpha constitutively stable beta subunit (ARNT). There are three HIF-alpha genes in mammals: HIF-1alpha, HIF-2alpha and HIF-3alpha. HIF-1alpha and HIF-2alpha have high primary sequence identity, although the target gene specificity of HIF-1 and HIF-2 is tissue-specific and non-identical. HIF-3alpha is quite different than HIF-1alpha and HIF-2alpha, particularly at its carboxy-terminus, and its target gene specificity is unknown. HIF-alpha dimerizes with ARNT and binds to hypoxia-responsive elements (HRE) in the enhancer/promoter regions of target genes to activate transcription. The von Hippel-Lindau tumour suppressor protein (pVHL) is the substrate recognition component of an E3 ubiquitin-ligase complex that targets HIF-lalpha and HIF-2alpha for degradation via the 26S proteasome in the presence of oxygen. VHL disease patients have an inherited mutation in VHL and frequently develop renal cell carcinomas (RCC). RCC-causing mutations of VHL render pVHL unable to recognize HIF-1alpha and HIF-2alpha, leading to accumulation of HIF-alpha and inappropriate transcription of targets that promote growth, spreading and survival of a solid tumour. Work contained within this thesis demonstrates that HIF-3alpha is also targeted for oxygen-dependent degradation via the pVHL E3 ubiquitin ligase complex, and that it is inappropriately stabilized in RCC with loss of functional VHL. As well, a splice isoform of HIF-3alpha, HIF-3alpha4, has been identified that has domain structure similarity to a dominant-negative splice variant of mouse HIF3alpha, IPAS. IPAS functions as a dominant-negative regulator of HIF-1 by binding to HIF-1alpha and forming abortive transcription complexes that are incapable of interacting with HRE. In contrast to IPAS, HIF-3alpha4 binds to HIF-1alpha, HIF-2alpha and ARNT, and inhibits DNA-binding and transactivation activity of HIF-1 and HIF-2. Inhibition of HIF-2-mediated transcription by adenoviral delivery of HIF-3alpha4 into human RCC xenografts in mice inhibits growth of the tumours, which exhibit decreased vascularity relative to those injected with control virus.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".