Complete loss of iron regulatory proteins 1 and 2 prevents viability of murine zygotes beyond the blastocyst stage of embryonic development

Smith, Sophia R.; Ghosh, Manik C.; Ollivierre‐Wilson, Hayden; Tong, Wing H.; Rouault, Tracey A.

doi:10.1016/j.bcmd.2005.12.006

Cited by 109 publications

(84 citation statements)

References 23 publications

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“…These results suggest that the redundancy in function in IRP1 serves to partly compensate for the absence of IRP2, which is consistent with mice lacking both IRP1 and IRP2 being embryonic lethal (Smith et al, 2006). We examined younger IRP2-/-mice to determine if changes in iron metabolism could be observed prior to the development of neurodegenerative symptoms and our findings are consistent with the report that IRP2-/-mice develop normally and symptoms are not seen until later in life (LaVaute et al, 2001).…”

Section: Discussionsupporting

confidence: 88%

Regional dissection and determination of loosely bound and non-heme iron in the developing mouse brain

et al. 2007

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Iron is a trace metal essential for normal brain development but toxic in excess as it is capable of generating highly reactive radicals that damage cells and tissue. Iron is stringently regulated by the iron regulatory proteins, IRP1 and IRP2, which regulate proteins involved in iron homeostasis at the posttranscriptional level. In this study, 12 distinct regions were microdissected from the mouse brain and regional changes in the levels of loosely bound and non-heme iron that occur with development were measured. We examined 6, 12, and 24 week old wildtype C57BL/6 mice and mice with a targeted deletion of iron regulatory protein 2 (IRP2-/-) that have been reported to develop neurodegenerative symptoms in adulthood. In wildtype mice, levels of loosely bound iron decreased while non-heme iron increased with development. In contrast, an increase in loosely bound and a more pronounced increase in non-heme iron was seen in IRP2-/-mice between 6 and 12 weeks of age, stemming from lower levels at 6 weeks (the youngest age examined) compared to wildtype. These results have implications for understanding the increase in regional brain iron that is associated with normal aging and is postulated to be exacerbated in neurodegenerative disorders.

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Section: Discussionsupporting

confidence: 88%

Regional dissection and determination of loosely bound and non-heme iron in the developing mouse brain

et al. 2007

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“…In addition to iron, the IREbinding of both IRPs can be influenced by hypoxia, nitric oxide, oxidative stress, and phosphorylation (for review, see Anderson et al 2012). The IRE-IRP system is essential, as indicated by the embryonic lethality of mice lacking both IRPs (Smith et al 2006;Galy et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Transferrin receptor mRNA interactions contributing to iron homeostasis

Rupani

Connell

2016

RNA

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The transferrin receptor is the primary means of iron importation for most mammalian cells and understanding its regulatory mechanisms is relevant to hematologic, oncologic, and other disorders in which iron homeostasis is perturbed. The 3 ′ UTR of the transferrin receptor mRNA contains an instability element that is protected from degradation during iron depletion through interactions of iron regulatory proteins (IRPs) with five iron-responsive elements (IREs). The structural features required for degradation and the site of IRP binding required for in situ protection remain unclear. An RNA-CLIP strategy is described here that identifies the predominant site of IRP-1 interaction within a nontransformed primary cell line. This approach avoided complications associated with the use of elevated concentrations of protein and/or mRNA and detected interactions within the native environment of the mRNA. A compensatory mutagenesis strategy indicates that the instability element at minimum consists of three non-IRE stem-loops that can function additively, suggesting that they are not forming one highly interdependent structure. Although the IREs are not essential for instability, they enhance instability when IRP interactions are inhibited. These results are supportive of a mechanism for a graded response to the intracellular iron resulting from a progressive loss of IRP protection.

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“…IRP1 and IRP2 are orthologous proteins that are largely but not completely functionally redundant. Underscoring the central need for appropriate regulation of iron metabolism in growth and development is the observation that genetic ablation of both IRP1 and IRP2 causes embryonic lethality in mice, and their intestinal function alone is essential (Galy et al 2005Smith et al 2006). In low iron, IRPs bind IREs, and when present in the 59 UTR, they block 43S ribosomal recruitment and hence mRNA translation (for review, see Muckenthaler et al 2008).…”

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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Complete loss of iron regulatory proteins 1 and 2 prevents viability of murine zygotes beyond the blastocyst stage of embryonic development

Cited by 109 publications

References 23 publications

Regional dissection and determination of loosely bound and non-heme iron in the developing mouse brain

Regional dissection and determination of loosely bound and non-heme iron in the developing mouse brain

Transferrin receptor mRNA interactions contributing to iron homeostasis

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

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