Stability of gastrointestinal glutathione peroxidase mRNA in selenium deficiency depends on its 3′UTR

Wingler, Kirstin; Müller, Cordula; Brigelius‐Flohé, Regina

doi:10.1002/biof.5520140107

Cited by 16 publications

(10 citation statements)

References 38 publications

(43 reference statements)

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“…On the other hand, stable selenoproteins are resynthesized faster upon selenium-resupplementation than unstable ones. A destabilization of GI-GPx mRNA was also observed when it was fused to cGPx 3'UTR (Wingler et al, 2001). Also in the family of glutathione peroxidases (GPx) a hierarchy has been observed which can be described as follows: GI-GPx ≥ PHGPx > cGPx = pGPx (Brigelius-Flohé, 1999).…”

supporting

confidence: 85%

3’UTRs of Glutathione Peroxidases Differentially Affect Selenium-Dependent mRNA Stability and Selenocysteine Incorporation Efficiency

Müller

Wingler²,

Brigelius‐Flohé³

2003

Biological Chemistry

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Selenoprotein mRNAs are particular in several aspects. They contain a specific secondary structure in their 3'UTR, called Secis (selenocysteine inserting sequence), which is indispensable for selenocysteine incorporation, and they are degraded under selenium-limiting conditions according to their ranking in the hierarchy of selenoproteins. In the familiy of selenium-dependent glutathione peroxidases (GPx) the ranking is GI-GPx > or = PHGPx > cGPx = pGPx. This phenomenon was studied by mutually combining the coding regions of GI-GPx, PHGPx and cGPx with their 3'UTRs. HepG2 cells were stably transfected with the resulting constructs. Expression of glutathione peroxidases was estimated by activity measurement and Western blotting, the selenium-dependent mRNA stability by real-time PCR. Whereas 3'UTRs from stable PHGPx and GI-GPx could be exchanged without loss of stability, they were not able to stabilize cGPx mRNA. cGPx 3'UTR rendered GI-GPx and PHGPx mRNA unstable. Thus, cGPx mRNA contains selenium-responsive instability elements in both the translated and the untranslated region, which cannot be compensated by one of the stable homologs. Stabilizing efficiency of an individual GPx 3'UTR did not correlate with the efficiency of selenocysteine incorporation. PHGPx 3'UTR was equally effective as cGPx 3'UTR in enhancing GPx activity in all constructs, while GI-GPx 3'UTR showed a markedly lower efficacy. We conclude that different mRNA sequences and/or RNA-binding proteins might regulate mRNA stability and translation of selenoprotein mRNA.

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supporting

confidence: 85%

3’UTRs of Glutathione Peroxidases Differentially Affect Selenium-Dependent mRNA Stability and Selenocysteine Incorporation Efficiency

Müller

Wingler²,

Brigelius‐Flohé³

2003

Biological Chemistry

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“…Several studies have found that the stability of GPx1 mRNA is enhanced by selenium repletion (11,31,32); however, not all selenoprotein mRNAs are affected by selenium levels (32,33). Transcript stability is often mediated by sequences such as "AU-rich" elements in the 3Ј-UTR of the mRNA (34).…”

Section: Discussionmentioning

confidence: 99%

Homocysteine Down-regulates Cellular Glutathione Peroxidase (GPx1) by Decreasing Translation

Handy

Zhang

Loscalzo

2005

Journal of Biological Chemistry

126

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Hyperhomocysteinemia contributes to vascular dysfunction and an increase in the risk of cardiovascular disease. An elevated level of homocysteine in vivo and in cell culture systems results in a decrease in the activity of cellular glutathione peroxidase (GPx1), an intracellular antioxidant enzyme that reduces hydrogen peroxide and lipid peroxides. In this study, we show that homocysteine interferes with GPx1 protein expression without affecting transcript levels. Expression of the selenocysteine (SEC)-containing GPx1 protein requires special translational cofactors to "read-through" a UGAstop codon that specifies SEC incorporation at the active site of the enzyme. These factors include a selenocysteine incorporation sequence (SECIS) in the 3-untranslated region of the GPx1 mRNA and cofactors involved in the biosynthesis and translational insertion of SEC. To monitor SEC incorporation, we used a reporter gene system that has a UGA codon within the protein-coding region of the luciferase mRNA. Addition of either the GPx1 or GPx3 SECIS element in the 3-untranslated region of the luciferase gene stimulated read-through by 6 -11-fold in selenium-replete cells; absence of selenium prevented translation. To alter cellular homocysteine production, we used methionine in the presence of aminopterin, a folate antagonist, co-administered with hypoxanthine and thymidine (HAT/Met). This treatment increased homocysteine levels in the media by 30% (p < 0.01) and decreased GPx1 enzyme activity by 45% (p ‫؍‬ 0.0028). HAT/Met treatment decreased selenium-mediated read-through significantly (p < 0.001) in luciferase constructs containing the GPx1 or GPx3 SECIS element; most importantly, the suppression of selenium-dependent read-through was similar whether an SV40 promoter or the GPx1 promoter was used to drive transcription of the SECIS-containing constructs. Furthermore, HAT/Met had no effect on steadystate GPx1 mRNA levels but decreased GPx1 protein levels, suggesting that this effect is not transcriptionally mediated. These data support the conclusion that homocysteine decreases GPx1 activity by altering the translational mechanism essential for the synthesis of this selenocysteine-containing protein.

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“…Levels of certain selenoproteins such as Sel P and DIO1 are more resistant to Se deficiency compared to others like GPx1, and regulation of these levels is mainly at the level of mRNA (Hill et al, 1992). There are differences even within the GPx subfamily (GPx1 through GPx4): Se deficiency leads to degradation of GPx1 and GPx3 mRNA before GPx2 and GPx4 mRNA (Weiss Sachdev and Sunde, 2001;Wingler et al, 2001;Muller et al, 2003). Under low Se conditions, the selenoprotein mRNAs are degraded through a process termed non-sense mediated decay (Maquat, 2001;Weiss Sachdev and Sunde, 2001), but transcriptional regulation or protein turnover must also be considered as points of regulation of selenoprotein levels.…”

Section: The Effect Of Decreased Selenium (Se) Intake On Selenoproteimentioning

confidence: 96%

The role of dietary selenium in inflammation and immunity

Huang¹,

China²,

Hoffmann³

2013

Diet, Immunity and Inflammation

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Stability of gastrointestinal glutathione peroxidase mRNA in selenium deficiency depends on its 3′UTR

Cited by 16 publications

References 38 publications

3’UTRs of Glutathione Peroxidases Differentially Affect Selenium-Dependent mRNA Stability and Selenocysteine Incorporation Efficiency

3’UTRs of Glutathione Peroxidases Differentially Affect Selenium-Dependent mRNA Stability and Selenocysteine Incorporation Efficiency

Homocysteine Down-regulates Cellular Glutathione Peroxidase (GPx1) by Decreasing Translation

The role of dietary selenium in inflammation and immunity

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