Figure 1
HIF-1 and/or p53 regulated genes mediating adaptation to cellular stresses through activation of different pathways. Upon hypoxia, the interaction between HIF-1α and von Hippel Lindau protein (pVHL) is disrupted, leading to HIF-1α translocation into nucleus, dimerization with HIF-1β subunit and formation of HIF-1 active form, which can regulate transcription of target genes . HIF-1 activates lactate dehydrogenase (LDH-A), pyruvate dehydrogenase kinase 1 (PDK1), phosphoglycerate mutase (PGM) and glucose transporter 1 (GLUT-1) to switch into more glycolytic phenotype [25]. To prevent apoptosis, it induces survivin expression [25] and downregulates BAX, BID and caspases activity [26]. HIF-1 can also induce autophagy by upregulation of beclin-1, BNIP3 and NIX [81]. Through modulating vascular endothelial growth factor (VEGF) [18], angiopioetin-2 (Ang-2) [25], carbonic anhydrase IX (CA IX) [12] and p21WAF1[90] expression, HIF-1 triggers activation of pro-survival pathways. Different molecular stresses (including DNA damage, hypoxia, oxidative stress), cause dissociation of p53 from murine double minute 2 (MDM2) complex, enabling its binding to regulatory elements of target genes [31]. Thereby p53 can repress glycolysis by altering expression of GLUT-1, PGM, TP53-induced glycolysis and apoptosis regulator (TIGAR) and inhibits pentose phosphate pathway by downregulating glucose-6-phosphate dehydrogenase (G6PDH) [36]. p53 regulates expression of many pro-apoptotic proteins, including PUMA, NOXA, CD95, Apaf1, BAX, BID and caspases [28]. Induction of autophagy by p53 relies on activation of damage-regulated autophagy modulator (DRAM) [83], sestrin 1, sestrin 2 and AMP-dependent kinase (AMPK) [84], but depending on cellular localization it can also inhibit this process [86]. Regulation the expression of transcription factor ATF3 enables adaptation to hypoxia, ER stress, oxidative stress and genotoxic stress [38], whereas during hypoxia induction of p21WAF1 causes cell cycle arrest [102]. p53 suppresses Akt-mTOR axis by transactivation of PTEN, TSC2 and AMPKβ1 [36].