Disease relevance of EPAS1

• Exposure of cultured A549 cells to hypoxia increased EPAS1 mRNA and protein levels [1].
• We showed that EPAS1, but not HIF-1alpha, is abundantly expressed in human lung adenocarcinoma A549 cells [1].
• No apparent correlation was observed between HIF-2alpha/EPAS1 and capsular formation, presence of cirrhosis, and histological grade [2].
• Expression of HIF-1{alpha}, HIF-2{alpha} (EPAS1), and Their Target Genes in Paraganglioma and Pheochromocytoma with VHL and SDH Mutations [3].
• Nox4 is critical for hypoxia-inducible factor 2-alpha transcriptional activity in von Hippel-Lindau-deficient renal cell carcinoma [4].

High impact information on EPAS1

• Their sequences are conserved between HLF and HIF1alpha [5].
• Recently, pVHL has been shown to regulate proteolysis of the transcription factors HIF-1 and HIF-2 (EPAS) [6].
• Real-time quantitative reverse transcriptase (RT)-PCR measurements confirmed that vascular endothelial growth factor and endothelial PAS domain protein 1 mRNA levels were significantly higher (three- and sixfold, respectively) than those observed in three sporadic benign pheochromocytomas [7].
• Thus, renal Nox4 expression is essential for full HIF2-alpha expression and activity in 786-0 renal tumor cells, even in the absence of functional VHL [4].
• Relation of hypoxia-inducible factor-2 alpha (HIF-2 alpha) expression in tumor-infiltrative macrophages to tumor angiogenesis and the oxidative thymidine phosphorylase pathway in Human breast cancer [8].

Chemical compound and disease context of EPAS1

• We also found that cytotrophoblasts upregulated the expression of bHLH/PAS factors that function in adaptive responses to hypoxia, including hEPAS-1, which is expressed primarily in endothelial cells [9].

Biological context of EPAS1

• Together, these data demonstrate Src family kinases mediate the hypoxia-mediated EPAS1 gene expression, which in turn positively autoregulates its own expression [1].
• Transient transfection assays revealed that EPAS1 increased PAI-1 gene transcription through a sequence containing 5'-CACGTACA-3' located at -194 (we refer to it as site HREPAI-1) and GT-box located at -78 [10].
• Electrophoretic gel mobility shift assays revealed that HREPAI-1 serves as a binding site for EPAS1, and Sp1 constitutively binds to GT-box [10].
• Transient transfection assays revealed that forced expression of EPAS1 increased the reporter gene activity driven by EPAS1 promoter as well as by VEGF promoter [1].
• These observations are consistent with transactivation by EPAS1 of the expression of its putative target genes during embryogenesis, suggesting that this transcription factor is involved in human angiogenesis [11].

Anatomical context of EPAS1

• EPAS1 was detected in all of the RCC cell lines examined [12].
• A parallel immunohistochemical analysis of VEGF demonstrated its positive correlation with capsule infiltration, portal vein invasion, and HIF-2alpha/EPAS1 overexpression, which supported the correlation of HIF-2alpha/EPAS1up-regulation with tumor angiogenesis [2].
• EPAS1 transcripts were detected in several types of endothelial cell: in blood vessels walls, the endocardium, the glomeruli of the mesonephros, and the sinusoids of the liver [11].
• There was also some overlap between the sites of synthesis of EPAS1 and VEGF mRNAs, principally in hepatocytes and sympathetic ganglion cells [11].
• Recent studies showed that EPAS1 is expressed in tumor associated macrophages (TAMs), which have multifaceted roles in tumor progression [13].

Associations of EPAS1 with chemical compounds

• BACKGROUND: Endothelial PAS domain protein 1 (EPAS1) is a basic helix-loop-helix/PAS domain transcription factor that expressed most abundantly in highly vascularized organs [12].
• METHODS: Complete cDNA of EPAS1 was cloned and transfected to cells from the 293 Tet-Off fetal kidney cell line, in which the expression of EPAS1 can be inhibited by doxycycline [12].
• Transcription Factor EPAS1 Regulates Insulin Signaling Pathway [14].
• In vitro DNA binding and mammalian two-hybrid assays showed that a unique cysteine in the DNA-binding basic region of HLF is a target for the reducing activity of redox factor Ref-1 [15].
• At 1% O2, HIF-2 alpha protein remained present in long-term cultures, while HIF-1 alpha was present only transiently [16].

Regulatory relationships of EPAS1

• CONCLUSIONS: These results suggest that endogenous VEGF can be up-regulated transcriptionally by EPAS1, and EPAS1 may be involved in the angiogenesis of RCC [12].
• In conclusion, PAI-1 expression is induced by EPAS1 through HREPAI-1 and through an Sp1-binding site [10].
• The results indicate that the direct interaction of Int6 induces proteasome inhibitor-sensitive HIF-2 alpha degradation [17].

Other interactions of EPAS1

• Both HIF-1 alpha and HIF-2 alpha protein and mRNA were up-regulated in primary human bladder tumors (n = 12) compared with normal bladder specimens (n = 4), with significant intertumor variation [18].
• These results suggest that components of the hypoxia response pathway, including HIF-1 alpha and HIF-2 alpha, are important cofactors in the regulation of VEGF in bladder cancer and are therapeutic targets in this disease [18].
• The PAI-1 gene as a direct target of endothelial PAS domain protein-1 in adenocarcinoma A549 cells [10].
• Expression of HIF-2alpha/EPAS1 in hepatocellular carcinoma [2].
• Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha target gene in Hep3B and Kelly cells [19].

Analytical, diagnostic and therapeutic context of EPAS1

• In situ hybridization showed that EPAS1 and VEGF were coexpressed topographically in tumor tissues [12].
• OBJECTIVE: To investigate whether anemia, a putative factor counteracting the efficacy of radiotherapy, up-regulates the endogenous markers of intratumoral hypoxia, the hypoxia inducible factors HIF1 alpha and HIF2 alpha [20].
• METHODS: Two bladder cancer cell lines (T24, EJ-1) were examined for the expression of HIF-2alpha/EPAS1 mRNA by reverse transcriptase-polymerase chain reaction and HIF-2alpha/EPAS1 protein by Western blot analysis, respectively [21].
• Multiple gene expression levels were evaluated using cDNA arrays in a human hepatocellular carcinoma cell line (HLF) with suppression of the VEGF-A gene by anti-VEGF-A ribozyme (alphaVRz) [22].
• E2A/HLF fusion cDNAs and the use of RT-PCR for the detection of minimal residual disease in t(17;19)(q22;p13) acute lymphoblastic leukemia [23].

References