An in silico model for HIF-alpha regulation and hypoxia response in tumor cells.
The dependency of the growth and metastasis of tumors on the new blood vessel formation, or angiogenesis, has opened up new potentials to tumor therapy, nevertheless understanding the molecular mechanisms involved in angiogenesis is crucial in the bioengineering of novel anti-angiogenic drugs. The key component in hypoxia sensing in tumor cells is the hypoxia-inducible factor, HIF-1alpha, which is inactivated through proteosome-mediated degradation under normoxic conditions. Two enzymes have been reported to hydroxylate HIF-1alpha, namely prolyl hydroxylase (PH), recruiting the proetasome complex and degrading cytoplasmic HIF-1alpha, and asparaginyl hydroxylase/factor inhibiting HIF-1alpha (FIH-1), downregulating the recruitment of p300 to the promoter, thereby reducing the transcriptional activity of HIF-1alpha. In this study, we have constructed an in silico model of a tumor cell using the GEPASI 3.30 biochemical simulation software (http://www.gepasi.org) and studied the performances of PH and FIH-1 on HIF-1alpha degradation and inactivation, respectively, as monitored by expression of the vascular endothelial growth factor, VEGF, during hypoxia. In our biochemical models, FIH-1 can successfully increase hypoxic transcription of VEGF, however FIH-1 on its own is not sufficient to inactivate HIF-1 completely, leading to background VEGF transcription under normoxic conditions. On the other hand, PH is necessary to increase the hypoxic transcriptional response, and can effectively shut off normoxic transcription. We therefore propose that regulating PH activity can be a primary target for anti-angiogenic bioengineering research.
Yucel
Meryem A
MA
Bogazici University, Institute of Biomedical Engineering, Bebek, Istanbul, Turkey.
Kurnaz
Isil Aksan
IA
D019295:Computational Biology; D003198:Computer Simulation; D015972:Gene Expression Regulation, Neoplastic; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics*; D008954:Models, Biological; D014407:Tumor Cells, Cultured
D051795:Hypoxia-Inducible Factor 1, alpha Subunit