HRF, a putative basic helix-loop-helix-PAS-domain transcription factor is closely related to hypoxia-inducible factor-1α and developmentally expressed in blood vessels

Abstract

Transcription factors of the bHLH-PAS protein family are important regulators of developmental processes such as neurogenesis and tracheal development in invertebrates. Recently a bHLH-PAS protein, named trachealess (trl) was identified as a master regulator of tracheogenesis. Hypoxia-inducible factor, HIF-1 alpha, is a vertebrate relative of trl which is likely to be involved in growth of blood vessels by the induction of vascular endothelial growth factor (VEGF) in response to hypoxia. In the present study we describe mRNA cloning and mRNA expression pattern of mouse HIF-related factor (HRF), a novel close relative of HIF-1 alpha which is expressed most prominently in brain capillary endothelial cells and other blood vessels as well as in bronchial epithelium in the embryo and the adult. In addition, smooth muscle cells of the uterus, neurons, brown adipose tissue and various epithelial tissues express HRF mRNA as well. High expression levels of HRF mRNA in embryonic choroid plexus and kidney glomeruli, places where VEGF is highly expressed, suggest a role of this factor in VEGF gene activation similar to that of HIF-1 alpha. Given the similarity between morphogenesis of the tracheal system and the vertebrate vascular system, the expression pattern of HRF in the vasculature and the bronchial tree raises the possibility that this family of transcription factors may be involved in tubulogenesis.

HIF-2α specifically activates the VE-cadherin promoter independently of hypoxia and in synergy with Ets-1 through two essential ETS-binding sites

“…The HIF-1a homolog HIF-2a was originally characterized as being preferentially expressed in endothelial cells of highly vascularized tissues during development and in the adult (Ema et al, 1997;Flamme et al, 1997;Tian et al, 1997;Jain et al, 1998). As for HIF-1a, the stability of the protein is increased in hypoxic conditions, whereas expression of the messenger RNA is not affected by variations in O 2 levels (Wiesener et al, 1998).…”

Coexpression of endothelial PAS protein 1 with essential angiogenic factors suggests its involvement in human vascular development

“…HIFs are heterodimeric factors composed of an ␣ subunit that is specifically induced in hypoxic conditions and a ␤ subunit (the aryl hydrocarbon receptor nuclear translocator [ARNT]) that is constitutively and ubiquitously produced. Three types of HIF␣ subunit have been identified in mammals: (1) HIF1␣ (Wang et al, 1995); (2) EPAS1 (Tian et al, 1997), also called HIF2␣, MOP2 (Hogenesch et al, 1997), HLF (Ema et al, 1997), and HRF (Flamme et al, 1997); and (3) the recently identified HIF3␣ . HIF1␣ is widely produced in the embryo (Jain et al, 1998) and activates a variety of genes involved in several hypoxia-responsive pathways such as angiogenesis, erythropoiesis, and glycolysis (for review see Semenza, 2000).…”

“…Gene targeting experiments have clearly demonstrated that HIF1␣ is required for embryonic vascularization, as major defects in early vascular de-velopment were observed in homozygous mice lacking HIF1␣ (Iyer et al, 1998, Ryan et al, 1998. EPAS1 displays a more restricted expression pattern (Flamme et al, 1997, Jain et al, 1998, Elvert et al, 1999, Favier et al, 1999 and is detected mostly in the vasculature during embryonic development. In vitro studies have shown that it can transactivate the synthesis of VEGF (Ema et al, 1997), its receptor VEGFR-2 , and the angiopoietin receptor Tie2 (Tian et al, 1997).…”

Targeting the hypoxic response in bone tissue engineering: A balance between supply and consumption to improve bone regeneration

“…There are three known HIF-a subunits, of which HIF-1a is the best studied. HIF-2a undergoes the same proteolytic degradation and appears to regulate a set of genes overlapping with HIF-1a (Flamme et al, 1997), but it also controls specific target genes and differs from HIF-1a in its spatial expression pattern, indicating that HIF-2a may act on different processes (Ema et al, 1997;Hu et al, 2003;Wiesener et al, 2003). With respect to skeletal development and homeostasis, both factors have been shown to regulate these processes differentially (Saito et al, 2010;Shomento et al, 2010).…”