Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells.

Abstract

Here we describe the cloning and characterization of a PAS domain transcription factor termed endothelial PAS-1 (EPAS1). This protein shares 48% sequence identity with hypoxia inducible factor (HIF-I~) and lesser similarity with other members of the basic helix-loop-helix/PAS domain family of transcription factors. Like HIF-lc~, EPAS1 binds to and activates transcription from a DNA element originally isolated from the erythropoietin gene and containing the sequence 5'-GCCCTACGTGCTGTCTCA-3'. Activation by both HIF-I~ and EPAS1 is stimulated by hypoxic conditions. EPAS1 forms a heterodimeric complex with the aryl hydrocarbon nuclear transporter prior to transcriptional activation of target genes. EPAS1 expression is limited to the endothelium of mouse embryos and, in agreement with its cell type-specific expression pattern, is capable of specifically activating the transcription of the endothelial tyrosine kinase gene Tie-2. These observations raise the possibility that EPAS1 may represent an important regulator of vascularization, perhaps involving the regulation of endothelial cell gene expression in response to hypoxia.[Key Words: PAS domain proteins; endothelial cell transcription; receptor tyrpsine kinase; Tie-2; hypoxia inducible factor; chromosome 2p [16][17][18][19][20][21]

The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2α

“…All constructs were verified by sequencing. The expression plasmids pCEP4-HIF-1a and pcDNA3-HIF-2a and the 5xHRE/hCMVmp-luc reporter construct were previously described (Forsythe et al, 1996;Tian et al, 1997;Shibata et al, 1998). Full-length HIF-2a-Flag was constructed by digestion of pcDNA3-HIF-2a using BamHI and cloning into the p3XFLAG-CMVt-10 expression vector (Sigma, St Louis, MO, USA).…”

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

“…In the dimeric, active state, HIF-1 and HIF-2 bind to hypoxia responsive elements (HREs) located in genes regulated by hypoxia and HIFs. Although HIF-1 and HIF-2 seem to activate hypoxiaresponsive genes by similar means (Tian et al 1997;Wiesener et al 1998), the HIF-α subunits work in a non-redundant manner and several differences in gene regulation have been proposed, many of which emphasize the predominant role of HIF-1 in regulating the transcriptional response to hypoxia (Iyer et al 1998;Ryan et al 1998;Hu et al 2003;Park et al 2003;Sowter et al 2003). As detailed below, HIF-2 is also crucial for the hypoxic response, and, as opposed to HIF-1, it is active at prolonged hypoxia as well (HolmquistMengelbier et al 2006).…”

Genome-wide identification and annotation of HIF-1α binding sites in two cell lines using massively parallel sequencing

“…During this process, glucose uptake is enhanced, angiogenesis is induced to obtain a sufficient blood supply, and cell migration is promoted (Harris 2002;Pouyssegur et al 2006;Gatenby and Gillies 2004;Hirota and Semenza 2006;Keith and Simon 2007). The central regulators of these changes in gene expression, which collectively lead to changes in cellular responses, are the transcription factors hypoxia-inducible factors 1 and 2 (HIF-1/2) (Wang and Semenza 1995;Tian et al 1997). Both HIF-1 and HIF-2 consist of two subunits, HIFa and HIF-b (or ARNT).…”