PubMed · 16282179
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E Kenneth Weir, José López-Barneo, Keith J Buckler, Stephen L Archer. 2005-11-10. Acute oxygen-sensing mechanisms.. https://doi.org/10.1056/nejmra050002
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Low oxygen levels are a defining characteristic of solid tumors, and responses to hypoxia contribute substantially to the malignant phenotype. Hypoxia-induced gene transcription promotes characteristic tumor behaviors, including angiogenesis, invasion, metastasis, de-differentiation and enhanced glycolytic metabolism. These effects are mediated, at least in part, by targets of the hypoxia-inducible factors (HIFs). The HIFs function as heterodimers comprising an oxygen-labile alpha-subunit and a stable beta-subunit also referred to as ARNT. HIF-1alpha and HIF-2alpha stimulate the expression of overlapping as well as unique transcriptional targets, and their induction can have distinct biological effects. New targets and novel mechanisms of dysregulation place the HIFs in an ever more central role in tumor biology and have led to development of pharmacological inhibitors of their activity.
PHD1-3 (prolyl hydroxylases 1-3) catalyse the hydroxylation of HIF (hypoxia-inducible factor)-alpha subunit that triggers the substrate ubiquitination and subsequent degradation. The RING (really interesting new gene) finger E3 ligase Siah2 preferentially targets PHD3 for degradation. Here, we identify the requirements for such selective targeting. Firstly, PHD3 lacks an N-terminal extension found in PHD1 and PHD2; deletion of this domain from PHD1 and PHD2 renders them susceptible to degradation by Siah2. Secondly, PHD3 can homo- and hetero-multimerize with other PHDs. Consequently, PHD3 is found in high-molecular-mass fractions that were enriched in hypoxia. Interestingly, within the lower-molecular-mass complex, PHD3 exhibits higher specific activity towards hydroxylation of HIF-1alpha and co-localizes with Siah2, suggesting that Siah2 limits the availability of the more active form of PHD3. These findings provide new insight into the mechanism underlying the regulation of PHD3 availability and activity in hypoxia by the E3 ligase Siah2.
Tumour hypoxia is a known cause of clinical resistance to radiation therapy. The purpose of this work was to model the effects on tumour control probability (TCP) of selectively boosting the dose to hypoxic regions in a tumour, while keeping the mean tumour dose constant. A tumour model with a continuous oxygen distribution, incorporating pO(2) histograms published for head and neck patients, was developed. Temporal and spatial variations in the oxygen distribution, non-uniform cell density and cell proliferation during treatment were included in the tumour modelling. Non-uniform dose prescriptions were made based on a segmentation of the tumours into four compartments. The main findings were: (1) Dose redistribution considerably improved TCP for all tumours. (2) The effect on TCP depended on the degree of reoxygenation during treatment, with a maximum relative increase in TCP for tumours with poor or no reoxygenation. (3) Acute hypoxia reduced TCP moderately, while underdosing chronic hypoxic cells gave large reductions in TCP. (4) Restricted dose redistribution still gave a substantial increase in TCP as compared to uniform dose boosts. In conclusion, redistributing dose according to tumour oxygenation status might increase TCP when the tumour response to radiotherapy is limited by chronic hypoxia. This could potentially improve treatment outcome in a subpopulation of patients who respond poorly to conventional radiotherapy.