Disease relevance of Egln3

• Recent findings show a homology of SM-20 with enzymes involved in the regulation of hypoxia inducible factor 1 [1].
• Hypoxia-inducible factor (HIF)-alpha subunits (HIF-1alpha, HIF-2alpha and HIF-3alpha), which play a pivotal role during the development of hypoxia-induced pulmonary hypertension (HPH), are regulated through post-translational hydroxylation by their three prolyl hydroxylase domain-containing proteins (PHD1, PHD2 and PHD3) [2].

High impact information on Egln3

• SM-20 is expressed at high levels in tissues and cells derived from muscle (smooth, skeletal, and cardiac) and nerve (brain, PC12 cells) and is not expressed in 3T3 fibroblasts or rat 6 fibroblasts [3].
• SM-20 encodes a new member of the immediate early gene family and is unusual in that it is expressed in vascular smooth muscle, but not in fibroblasts [3].
• SM-20 levels increase within 1 h of treatment with growth agonists (serum, platelet-derived growth factor, angiotensin II), isoproterenol, and forskolin [3].
• SM-20 encodes an mRNA of approximately 2.5-3.0 kilobase pairs which is present at low levels in quiescent vascular smooth muscle cells [3].
• We have employed differential screening of a rat aortic smooth muscle cell cDNA library to isolate a cDNA clone, SM-20, whose nucleotide and deduced amino acid sequences are distinct from those reported previously [3].

Biological context of Egln3

• This increase is likely caused by a downregulation of SM-20/PHD3 [4].
• Induction of SM-20 in either undifferentiated or NGF-differentiated cells resulted in cell death [5].
• In transient transfections, the SM-20 promoter displayed approximately 6-fold greater activity in smooth muscle cells vs. fibroblasts [6].

Anatomical context of Egln3

• Analysis of cytochrome c in cytosolic and mitochondria-enriched subcellular fractions revealed that induction of SM-20 led to the accumulation of cytochrome c in the cytosol [5].
• To further evaluate the mechanism by which SM-20 promotes cell death, we developed a PC12-derived cell line in which SM-20 expression can be induced by addition of doxycycline to the culture medium [5].
• A rabbit polyclonal antibody was generated against a peptide sequence of SM-20 and detected a major band of the predicted size of 40 kd and a second 33-kd band that likely represents a processed form present in mitochondria [1].

Associations of Egln3 with chemical compounds

• Cycloheximide induces high levels of SM-20 mRNA and superinduces it in the presence of serum, suggesting that the increase in SM-20 mRNA levels is not dependent on protein synthesis and is part of the primary response to growth agonists [3].
• Expression of SM-20 also increases during neuronal death caused by cytosine arabinoside or the phosphatidylinositol 3-kinase inhibitor LY294002 [7].

Regulatory relationships of Egln3

• These results suggest that SM-20 promotes caspase-dependent cell death through a mechanism involving cytochrome c [5].

Other interactions of Egln3

• A reduction in SM-20/PHD3 mRNA expression paralleled the increase in HIF-1 alpha [4].
• Induction of SM-20 in PC12 cells leads to increased cytochrome c levels, accumulation of cytochrome c in the cytosol, and caspase-dependent cell death [5].

Analytical, diagnostic and therapeutic context of Egln3

• Immunohistochemistry revealed a granular staining of the cytoplasm of PC12 cells compatible with a previously described mitochondrial localization of SM-20 protein [1].
• ANG II suppressed mRNA expression of SM-20 in PC12 cells after only 30 minutes, as detected by Northern blotting [1].
• Subsequent sequence analysis of T19 revealed a high degree of similarity to the 3' untranslated region of a rat growth factor responsive gene, SM-20 [8].

References