Redox Regulation of a Novel L1Md-A2 Retrotransposon in Vascular Smooth Muscle Cells

Abstract

Activation and reintegration of retrotransposons into the genome is linked to several diseases in human and rodents, but mechanisms of gene activation remain largely unknown. Here we identify a novel gene of L1Md-A2 lineage in vascular smooth muscle cells and show that environmental hydrocarbons enhance gene expression and activate monomer-driven transcription via a redox-sensitive mechanism. Site-directed mutagenesis and progressive deletion analyses identified two antioxidant/electrophile response-like elements (5-GTGACTCGAGC-3) within the A2/3 and A3 region. These elements mediated activation, with the A3 monomer playing an essential role in transactivation. This signaling pathway may contribute to gene instability during the course of atherogenesis.

Activation of Human Long Interspersed Nuclear Element 1 Retrotransposition by Benzo(a)pyrene, an Ubiquitous Environmental Carcinogen

“…Expression of L1 retrotransposon sequences is up-regulated in mouse somatic cells challenged acutely with BaP or its oxidative metabolites as determined by Northern blot analysis, differential display, and realtime PCR (27)(28)(29). To determine if BaP treatment activates human L1 expression and increases L1 retrotransposition, a plasmid-based strategy was employed using cultured HeLa cells.…”

“…Previously, we reported that expression of L1 retrotransposon sequences is dramatically up-regulated in mouse vascular smooth muscle cells challenged with BaP or its oxidative metabolites as determined by Northern blot analysis, differential display, and DNA microarrays (27)(28)(29). Moreover, a novel retrotransposon of mouse L1Md-A2 lineage was found in vascular smooth muscle cells that contain two antioxidant responsive elements in its 5V -UTR region and participate in transactivation (29).…”

“…Moreover, a novel retrotransposon of mouse L1Md-A2 lineage was found in vascular smooth muscle cells that contain two antioxidant responsive elements in its 5V -UTR region and participate in transactivation (29). Insertion of this 5V -UTR upstream of a reporter gene increases reporter gene expression 2-fold in response to the genotoxic carcinogen BaP and the nongenotoxic carcinogen TCDD.…”

“…We have shown previously that benzo(a)pyrene (BaP), a polycyclic aromatic hydrocarbon carcinogen, activates L1 expression in various cell types (27)(28)(29). L1 activation by BaP requires cytochrome P450-catalyed oxidation of the parent hydrocarbon to oxygenated intermediates that adduct DNA (28).…”

EZR1: A Novel Family of Highly Expressed Retroelements Induced by TCDD and Regulated by a NF-κB-Like Factor in Embryos of Zebrafish (Danio rerio)

“…48,52 Particularly interesting is the correlation between elevated levels of certain endogenous retroviral transcripts in myocardium and cardiovascular disease in rats, 53,54 and the suggestion that L1Md may be involved in atherogenesis. 55 EZR1 transcript abundances were dose-dependently increased by doses of TCDD that cause cardiovascular toxicity and disrupted cardiomyocyte gene expression. 4 Regardless, the evidence indicates that TCDD induction of EZR1 involves activation of a zebrafish NF-jB-like factor.…”