Activation of hypoxia-inducible factor 1 alpha by oxygen independent pathways

The increasing body of evidence supports that hypoxia-inducible factor 1 al pha (HIF-1 alpha) a dominant subunit of HIF-1 heterodimer, is not solely in duced by the effect of hypoxia. Apart from CoCl2 and iron chelators that se rve as the putative HIF-1 alpha activators, genetic alterations and other e pigenetic effects are able to induce HIF-1 alpha protein accumulation and t o activate HIF-1 functions. Activation of oncogenes (H-ras and v-src) invol ving signaling cascades (PI3K and MAPK) and loss-of-function mutations in t umor suppressor genes (VHL, PTEN, and p53) result in HIF-1 alpha protein ac cumulation and increased expression of downstream target genes. HIF-1 alpha can also be induced by a number of agonists. Activation of HIF-1 alpha is often an interactive consequence of multiple factors.