Hypoxia-inducible factor.


Hypoxia is a condition where physiologic oxygen levels fall lower than the normal, which can result in stroke, brain injury, spinal cord injury, other neurodegenerative diseases, and cancer. Because of the importance of oxygen for life, organisms have developed mechanisms to cope and survive low oxygen levels (hypoxia). During hypoxia, cells adapt by altering the expression of many genes: those involved in maintaining oxygen homeostasis, coping with reactive oxygen species and other effects of low oxygen stress. Many of these genes are directly regulated by the hypoxia-inducible transcription factor (HIF. with common isoforms: HIF-1 and HIF-2). When oxygen levels are normal (normoxia), HIF is barely discernible. under hypoxia the HIF concentration increases dramatically. The active form of HIF is composed of two sub-units, HIF α, and HIF β. The latter is constitutively expressed regardless of physiologic oxygen concentration, while HIF α concentration is very low under normoxic conditions but increases with hypoxia. In normoxia, HIF α is hydroxylated by through the action of prolyl hydroxylases domain proteins or PHD. Hydroxylation allows HIF α to associate with a protein complex that makes it a target for proteolytic degradation. The proof of the inhibitory effect of PHD on HIF was established when silencing of PHD2 gene increased normoxic HIF levels (Berraet al., 2003). Silencing of other identified PHD, 1 and 3, did not affect normoxic levels of HIF, leading to the conclusion that the PHDs have different roles in vivo (Berra et al., 2003).

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