Fig. 3.
A. Regulation of the hypoxia-inducible transcription factor 1α (HIF-1α). HIF-1 is a heterodimer transcription factor that consists of an O2-sensitive α subunit and a constitutively expressed β subunit. The level of HIF-1α is determined by the relative ratio of its synthesis versus degradation. Under normoxic conditions HIF-1α is quickly degraded and exhibits a half-life of just about 5 min. HIF-1α is hydroxylated and rapidly degraded by the ubiquitin-proteasome pathway. HIF-1α stability is regulated via the activity of a class of oxygen-, 2-oxoglutarate-, and iron-dependent enzymes known as prolyl-4-hydroxylases (PDH), which hydroxylate two prolines at locations 402 or 564. Hydroxylation of HIF-1α created a recognition site VHL, a E3 ubiquitin ligase adapter recruits HIF-1α to the VHL-elongin B and C-Cul2 complex. Thus, VHL directs ubiquitination and subsequent proteasomal degradation of HIF-1α. By contrast, under oxygen-limiting conditions, HIF-1α is stabilized, and can translocate to the nucleus where it dimerizes with HIF-1β and activates transcription of genes containing hypoxia response elements (HREs). These genes include those that enhance hypoxia tolerance by increasing oxygen delivery to the tissues and anaerobic ATP-generation by glycolysis. B, Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master regulator transcription factor of redox homeostasis that functions in association with ‘small’ Maf proteins. Under basal redox conditions, NRF2 is localized in cytoplasm in association with Kelch ECH associating protein 1 (Keap1) and has a very short half life of about 20 min. The Keap1-Cul3-Rbx complex directs polyubiquitination of the Nrf2 and its subsequent proteasomal degradation. However, under oxidative or electrophilic conditions, specific Cys residues of Keap1 undergo oxidative modification. Bound NRF2 is not degraded and newly synthesized NRF2 is able to accumulate, translocate to the nucleus and induce the expression of target genes. In the nucleus Nrf2 drives the expression of genes containing an enhancer termed Antioxidant Response Element (ARE) such NAD(P)H quinone oxidoreductase 1, heme oxygenase 1, catalase, CuZn superoxide dismutase, glutamate-cysteine ligase, glutathione S-transferases, etc. C, The UPS plays also a role in activation of NFκB. According to canonical pathway of NFκB activation, ubiquitination and proteasomal degradation of its inhibitor (IκBα) releases NFκB, which now can freely translocate into nucleus. In this way, NFκB can activate transcription of genes vital for cellular response to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, and bacterial or viral antigens.