Bibliographic record
Abstract
Factor Inhibiting Hypoxia-inducible Factor (FIH) is an asparaginyl hydroxylase which regulates the transcription factor Hypoxia-Inducible Factor (HIF), via hydroxylation of a conserved asparagine residue of the HIF-alpha subunits (two isoforms of which are well established, HIF-1 and HIF-2alpha – HIF-3alpha is less well characterized currently). Other targets of FIH have also been reported. Little is known about both FIH expression and function. This thesis will investigate the expression of FIH in rodents, in cell lines and in renal cancer tissue samples. In addition, RNAi technology was used to study FIH function. Clear cell renal cell carcinoma (CCRCC) is commonly associated with inactivation of tumour suppressor von-Hippel Lindau protein (VHL) and constitutive activation of HIF. The main question I have addressed in this thesis is whether FIH decreases HIF activation in this setting. To address this I inhibited FIH using several approaches. Specifically, using hypoxia, dimethyloxalylglycine (DMOG) and RNA interference (RNAi). Each of these increased the expression of HIF target genes in two different CCRCC cell lines, RCC10 and RCC4. Investigating three different CCRCC cell lines, FIH inhibition decreased numbers of RCC4 and RCC10 cells growing in culture, which is likely to be due to an increase in expression of pro-apoptotic, FIH-regulated HIF target genes. Interestingly, 786-O cells exclusively express the HIF-2alpha isoform. Attenuation of FIH in this setting did not affect expression of HIF target genes, nor affect growth in culture. To determine if this was due to lack of FIH or may be due to lack of HIF-1alpha, I introduced HIF-1alpha via a viral vector. Following this, sensitivity to FIH was clearly demonstrated. This implies either specific ‘protection’ of HIF-2alpha in 786-O or more general FIH selectivity for the HIF- 1alpha isoform. My findings contrast with two reports suggesting that FIH expression is suppressed in CCRCC. My findings give insight into how FIH asparagine hydroxylation regulates HIF, in particular in renal cancer and makes this enzyme a potential target for therapeutic inhibition, in the majority of renal cancers.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".