The family of iron responsive RNA structures regulated by changes in cellular iron and oxygen

Leipuviene, Ramune; Theil, Elizabeth C.

doi:10.1007/s00018-007-7198-4

Cited by 94 publications

(87 citation statements)

References 124 publications

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“…Another important feature of IREB2 is that it is suggested to be active at lower oxygen tensions 23 and has been observed to be post-translationally regulated by hypoxia. 24,25 Thus, the aberrant iron homeostasis in the presence of hypoxia could lead to increased oxidative stress resulting in tissue damage and reduced FEV 1 . Functional studies will be required to clarify the role of iron regulation in COPD pathogenesis in the future.…”

Section: Association Of Ireb2 and Chrna3/5 With Copd In A Chinese Hanmentioning

confidence: 99%

Association of IREB2 and CHRNA3/5 polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population

Zhou

Yang

et al. 2012

J Hum Genet

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Genome-wide association studies and integrative genomics approaches have demonstrated significant associations between chronic obstructive pulmonary disease (COPD) and single-nucleotide polymorphisms (SNPs) in the chromosome 15q25 region that includes iron-responsive element binding protein 2 gene (IREB2) and CHRNA3/5 in non-Asian populations. We investigated whether IREB2 and CHRNA3/5 polymorphisms would be associated with COPD susceptibility and COPD-related phenotypes in a Chinese Han population. Eight SNPs (rs2568494, rs2656069, rs10851906, rs1964678, rs12593229, rs965604, rs13180, rs17483929) in IREB2 gene and four SNPs (rs16969968, rs1051730, rs938682, rs8034191) in or near CHRNA3/5 locus were genotyped in a case-control study (680 COPD patients and 687 controls). No significant associations were found between any of the SNPs and COPD in either former-smokers or current-smokers. Two SNPs (rs2656069 and rs10851906) in IREB2 were associated with COPD (P ¼ 0.045 and 0.032, respectively) in non-smoker. Four SNPs (rs1964678, rs12593229, rs965604 and rs13180) in IREB2 were associated with forced expiratory volume in 1 s (FEV 1 )% predicted and three SNPs (rs16969968, rs8034191 and rs1051730) in CHRNA3/5 were both associated with FEV 1 % predicted and FEV 1 /FVC in COPD cases (P range 0.007-0.050). The SNP rs8034191 near CHRNA3/5 locus was significantly associated with pack-years of smoking in COPD patients (P ¼ 0.033). We demonstrated IREB2 polymorphisms were associated with COPD in non-smoking subjects, and the effect of IREB2 gene on COPD may be independent from smoking and independent from CHRNA3/5 gene cluster. Besides, we confirmed that SNPs in these two gene loci were associated with pulmonary function and CHRNA3/5 polymorphism was associated with pack-year of smoking in COPD patients in the Chinese Han population.

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Section: Association Of Ireb2 and Chrna3/5 With Copd In A Chinese Hanmentioning

confidence: 99%

Association of IREB2 and CHRNA3/5 polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population

Zhou

Yang

et al. 2012

J Hum Genet

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“…Iron regulatory proteins (IRPs) function as critical components of a sensory and regulatory network that controls cellular iron homeostasis in vertebrates (Wallander et al 2006; Leipuviene and Theil 2007;Muckenthaler et al 2008). IRPs bind iron-responsive elements (IREs) in the untranslated region of mRNA encoding proteins involved in iron metabolism, or in the adaptive response to changes in iron availability, and regulate their translation or stability.…”

Section: Introductionmentioning

confidence: 99%

“…To date six mammalian mRNAs encoding proteins of widely different function have been identified that possess 59 IREs. These mRNAs encode the erythroid-specific isoform of 5-aminolevulinate synthase (eALAS), which catalyzes the first step in heme synthesis; the H and L subunits of the iron storage protein ferritin; the iron exporter ferroportin; mitochondrial aconitase (m-acon), which is the second enzyme of the tricarboxylic acid cycle; and the hypoxia-inducible transcription factor HIF 2a (also known as EPAS1) (Wallander et al 2006;Leipuviene and Theil 2007;Muckenthaler et al 2008). Given the varied function of proteins encoded by mRNA containing 59 IREs, it seems likely that IRPs differentially control translation of these mRNAs.…”

Section: Introductionmentioning

confidence: 99%

Multiple determinants within iron-responsive elements dictate iron regulatory protein binding and regulatory hierarchy

Goforth¹,

Anderson²,

Nizzi³

et al. 2009

RNA

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Iron regulatory proteins (IRPs) are iron-regulated RNA binding proteins that, along with iron-responsive elements (IREs), control the translation of a diverse set of mRNA with 59 IRE. Dysregulation of IRP action causes disease with etiology that may reflect differential control of IRE-containing mRNA. IREs are defined by a conserved stem-loop structure including a midstem bulge at C8 and a terminal CAGUGH sequence that forms an AGU pseudo-triloop and N19 bulge. C8 and the pseudo-triloop nucleotides make the majority of the 22 identified bonds with IRP1. We show that IRP1 binds 59 IREs in a hierarchy extending over a ninefold range of affinities that encompasses changes in IRE binding affinity observed with human L-ferritin IRE mutants. The limits of this IRE binding hierarchy are predicted to arise due to small differences in binding energy (e.g., equivalent to one H-bond). We demonstrate that multiple regions of the IRE stem not predicted to contact IRP1 help establish the binding hierarchy with the sequence and structure of the C8 region displaying a major role. In contrast, base-pairing and stacking in the upper stem region proximal to the terminal loop had a minor role. Unexpectedly, an N20 bulge compensated for the lack of an N19 bulge, suggesting the existence of novel IREs. Taken together, we suggest that a regulatory binding hierarchy is established through the impact of the IRE stem on the strength, not the number, of bonds between C8 or pseudo-triloop nucleotides and IRP1 or through their impact on an induced fit mechanism of binding.

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“…Stewart G. Stevens, 1 Paul P. Gardner 2 and Chris M. Brown 1, tri-loop (A15, G16, U17) and that two bases (a C8 and U6) are bulged from the hairpin stem. These structures 9,10 did confirm the predicted secondary structure of an A-form helical stem, interrupted by a mid-stem C8 bulge, with an apical loop that presents conserved bases interacting with IRE binding proteins.…”

Section: Two Covariance Models For Iron-responsive Elementsmentioning

confidence: 99%

“…1 Since then, IREs have been found in both the 5' and 3' UTRs of diverse mRNAs over a wide phylogenetic range-mainly eukaryotic animals and also some prokaryotes, but not plants. 2 Iron regulatory proteins 1 and 2 (IRP1 and IRP2) bind to IREs in low iron conditions. In high iron conditions IRP1 binds to iron complexes, adopting conformations unsuitable for IRE binding.…”

Section: Introductionmentioning

confidence: 99%

Two covariance models for iron-responsive elements

Stevens¹,

Gardner²,

Brown³

2011

RNA Biology

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The family of iron responsive RNA structures regulated by changes in cellular iron and oxygen

Cited by 94 publications

References 124 publications

Association of IREB2 and CHRNA3/5 polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population

Association of IREB2 and CHRNA3/5 polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population

Multiple determinants within iron-responsive elements dictate iron regulatory protein binding and regulatory hierarchy

Two covariance models for iron-responsive elements

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