DNA and mRNA elements with complementary responses to hemin, antioxidant inducers, and iron control ferritin-L expression

Abstract

Ferritins, an ancient family of protein nanocages, concentrate iron in iron-oxy minerals for iron-protein biosynthesis and protection against oxy radical damage. Of the two genetic mechanisms that regulate rates of ferritin-L synthesis, DNA transcription and mRNA translation, more is known about mRNA regulation where iron targets complexes of an mRNA structure, the iron-responsive element (IRE) sequence, and ferritin IRE repressors (iron regulatory proteins 1 and 2). Neither the integration of mRNA and DNA regulation nor the ferritin-L DNA promoter are well studied. We now report the combined effects of DNA transcription and mRNA translation regulation of ferritin-L synthesis. First, the promoter of human ferritin-L, encoding the animal-specific subunit associated with human diseases, was identified, and contained an overlapping Maf recognition element (MARE) and antioxidant responsive element (ARE) that was positively regulated by tert-butylhydroquinone, sulforaphane, and hemin with responses comparable to thioredoxin reductase (ARE regulator) or quinone reductase (MARE͞ARE regulator). Iron, a poor regulator of the ferritin-L promoter, was 800 times less effective than sulforaphane. Combining the ferritin-L MARE͞ARE and IRE produced a response to hemin that was 3-fold greater than the sum of responses of the MARE͞ARE or IRE alone. Regulation of ferritin-L by a MARE͞ARE DNA sequence emphasizes the importance of ferritin-L in oxidative stress that complements the mRNA regulation in iron stress. Combining DNA and mRNA mechanisms of regulation, as for ferritin-L, illustrates the advantages of using two types of genetic targets to achieve sensitive responses to multiple signals.antioxidant responsive element ͉ Maf recognition element ͉ oxygen ͉ iron responsive element ͉ combinatorial regulation

Role and regulation of ferritin H in rotenone-mediated mitochondrial oxidative stress

“…In some instances where cellular oxidative load is increased, cells may be more susceptible to iron mediated production of ROS and damage. We, along with others, demonstrated that ferritin is upregulated in response to a battery of different oxidative stressors [14,15,17]. Overexpression of ferritin H in cells reduced free iron levels and increased cellular resistance to H 2 O 2 toxicity [27,28].…”

“…Our subsequent studies revealed an antioxidant responsive element (ARE) in the far upstream region of the promoter that is necessary for the transcriptional activation of the ferritin gene in response to various oxidative stressors, including H 2 O 2 , tBHQ (tertbutylhydroquinone), and hemin [14][15][16]. A similar ARE element was identified in ferritin L gene [17]. The ARE is a highly conserved enhancer element in various phase II genes involved in detoxification or with antioxidant properties, allowing for the activation of a battery of antioxidant genes including glutathione-S-transferases, NADH quinone oxidoreductase 1, and heme oxygenase 1 under chemical and oxidative stress conditions [18].…”

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

“…However heme was shown to be a strong inducer in some cellular systems: it acts by removing Bach1 repressor and permitting the binding of the transcription factor Nrf2 (Hintze and Theil 2006;Hintze et al 2007). Also oxidative stress induced a significant increase (up to 80 fold) in ferritin mRNA (Torti and Torti 2002;Hintze and Theil 2005). A combination of different repressor (Bach1 and ATF1) (Iwasaki et al 2007;Hintze et al 2007) and activators (Nrf2, JunD) (Iwasaki et al 2006;MacKenzie et al 2008) are involved in the recognition and binding of the Antioxidant Response Elements (ARE) in the promoter region of mouse ferritin H and L genes, modulating their expression in response to oxidative stimuli.…”

Heme-arginate suppresses phospholipase C and oxidative stress in the mesenteric arterioles of mineralcorticoid-induced hypertensive rats

“…27,28 In tissues, the antioxidant system comprises different enzymes, including superoxide dismutase, catalase and glutathione peroxidise, as well as substances such as ferritin, ascorbic acid, a-tocopherol, b-carotene, reduced glutathione, uric acid, biliverdin and bilirubin. [21][22][23][24][25][26]35 The sum of endogenous and food-derived antioxidants represents the total antioxidant activity of the system. The additive effect of all the different antioxidants provides greater protection against oxidative stress than any single compound alone.…”

“…19 The pharmacological upregulation of the HO system has been shown to combat hypertension, inflammation and oxidative stress. [20][21][22][23][24][25][26] By breaking down the heme moiety, HO removes the pro-oxidant heme 21 while carbon monoxide, bilirubin/biliverdin and ferritin scavenge reactive oxygen species, inhibit lipid peroxidation and suppress tissue inflammation. [22][23][24][25][26] Accordingly, carbon monoxide, bilirubin, bliverdin and ferritin constitute a protective tetrad against hypertension and its secondary damages including oxidative and inflammatory insults.…”