Disease relevance of EGLN2

• Expression of prolyl-hydroxylase-1 (PHD1/EGLN2) suppresses hypoxia inducible factor-1alpha activation and inhibits tumor growth [1].
• EIT-6 appears to be a direct transcriptional target of the estrogen receptor and constitutive expression of EIT-6 promotes colony growth in human breast cancer cells [2].
• Overexpression and nuclear translocation of hypoxia-inducible factor prolyl hydroxylase PHD2 in head and neck squamous cell carcinoma is associated with tumor aggressiveness [3].
• In a model of myocardial infarction, in situ hybridization showed periischemic enhancement for PHD2 mRNA and PHD3 mRNA, but not PHD1 mRNA [4].

High impact information on EGLN2

• Thus, the control of PHD1/3 by Siah1a/2 constitutes another level of complexity in the regulation of HIF1alpha during hypoxia [5].
• An absolute requirement for dioxygen as a cosubstrate and iron as cofactor suggests that HIF-PH functions directly as a cellular oxygen sensor [6].
• The significance of this finding was underscored by the fact that disease-causing missense mutations in the PHD1 (C311Y and P326Q) abolished its E3 ligase activity [7].
• Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2) [8].
• ING4 directly associates with the HIF prolyl hydroxylase, an Fe(II)-dependent oxygenase previously shown to mediate HIF stability as a function of oxygen availability [9].

Biological context of EGLN2

• Each of the human genes (EGLN1, EGLN2 and EGLN3) are of a conserved genomic structure consisting of five coding exons [10].
• EGLN1, EGLN2, and EGLN3 were also temporally expressed in an oxygen-dependent fashion, with greatest mRNA expression at 10-12 wk of gestation [11].
• Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro [12].
• Three enzymes, prolyl hydroxylase domain-containing proteins 1, 2, and 3 (PHD1, -2, and -3; also known as HIF prolyl hydroxylase 3, 2, and 1, respectively), have recently been identified that catalyze proline hydroxylation of HIF alpha subunits [13].
• Of the three HIF prolyl hydroxylases (PHD1, 2 and 3) identified, PHD3 exhibits restricted substrate specificity in vitro and is induced in different cell types by diverse stimuli [14].

Anatomical context of EGLN2

• Immunoreactivity for PHD1, PHD3, and seven in absentia homolog (SIAH)1 was noted in the pulmonary epithelium [15].
• Expression of HIF prolyl hydroxylase isozymes in growth plate chondrocytes: Relationship between maturation and apoptotic sensitivity [16].
• PHD1 and 3 mRNA distributions suggest particular roles in testis and heart, respectively [4].

Associations of EGLN2 with chemical compounds

• In these domain-swapping experiments, prolyl hydroxylase domain 1 (PHD1) and PHD2 preferentially hydroxylated the proline located in the site of the original 564 ODD, while PHD3 preferred the proline 564 sequence, regardless of its location [17].
• This modification is catalysed by an enzyme termed HIF-prolyl hydroxylase (HIF-PH), and compatible with all previously described prolyl-4-hydroxylases HIF-PH also requires 2-oxoglutarate as a cosubstrate [18].
• Surprisingly, a polybasic region that follows the PHD1 is necessary for PI(3)P binding [19].
• These data indicate that EIT-6 may play a role in estrogen induced cell growth [2].
• Although nPG did not inhibit the HIF prolyl hydroxylase, gallate, the hydrolysis product of nPG, inhibited the enzyme completely at submillimolar concentrations [20].

Other interactions of EGLN2

• Suppression of hypoxia-inducible factor 1alpha (HIF-1alpha) transcriptional activity by the HIF prolyl hydroxylase EGLN1 [21].
• Recent biochemical and candidate gene approach studies have led to the discovery of three HIF-regulatory prolyl hydroxylases, PHD-1, -2 and -3 and an asparaginyl hydroxylase, also known as FIH (factor inhibiting HIF) [22].
• Taken together, our findings suggest a hypoxia-induced regulatory loop of PHD1 expression, mediated by ARNT [23].
• By contrast, BAPTA-am exerted its effects via inhibition of HIF-prolyl hydroxylase activity and von Hippel-Lindau tumor repressor protein (VHL) interaction [24].
• PHI-1 treatment also increased PHD-2, but not PHD-1 or -3, protein [25].

References