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Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory prot

Discussion in 'Adrenal Rx and Leaky Gut Rx' started by chocolate, Apr 27, 2012.

  1. chocolate

    chocolate Silver

    Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis



    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1271751/



    Abstract

    The two iron regulatory proteins IRP1 and IRP2 bind to transcripts of ferritin, transferrin receptor and other target genes to control the expression of iron metabolism proteins at the post-transcriptional level. Here we compare the effects of genetic ablation of IRP1 to IRP2 in mice. IRP1−/− mice misregulate iron metabolism only in the kidney and brown fat, two tissues in which the endogenous expression level of IRP1 greatly exceeds that of IRP2, whereas IRP2−/− mice misregulate the expression of target proteins in all tissues. Surprisingly, the RNA-binding activity of IRP1 does not increase in animals on a low-iron diet that is sufficient to activate IRP2. In animal tissues, most of the bifunctional IRP1 is in the form of cytosolic aconitase rather than an RNA-binding protein. Our findings indicate that the small RNA-binding fraction of IRP1, which is insensitive to cellular iron status, contributes to basal mammalian iron homeostasis, whereas IRP2 is sensitive to iron status and can compensate for the loss of IRP1 by increasing its binding activity. Thus, IRP2 dominates post-transcriptional regulation of iron metabolism in mammals.

    Keywords: cytosolic aconitase, iron metabolism, iron regulatory protein 1 (IRP1), iron-responsive element (IRE)



    This is a great article with the discussions included.
     
  2. chocolate

    chocolate Silver

    http://home.ccr.cancer.gov/LOP/Clinical/ultrapath/msa_publications/Nat_Genet_Feb_2001.pdf



    Targeted deletion of the gene encoding iron regulatory

    protein-2 causes misregulation of iron metabolism and

    neurodegenerative disease in mice

    In mammalian cells, regulation of the expression of proteins

    involved in iron metabolism is achieved through interactions of

    iron-sensing proteins known as iron regulatory proteins (IRPs),

    with transcripts that contain RNA stem-loop structures referred

    to as iron responsive elements (IREs). Two distinct but highly

    homologous proteins, IRP1 and IRP2, bind IREs with high affinity

    when cells are depleted of iron, inhibiting translation of

    some transcripts, such as ferritin, or turnover of others, such as

    the transferrin receptor (TFRC). IRPs sense cytosolic iron levels

    and modify expression of proteins involved in iron uptake,

    export and sequestration according to the needs of individual

    cells1,2. Here we generate mice with a targeted disruption of

    the gene encoding Irp2 (Ireb2). These mutant mice misregulate

    iron metabolism in the intestinal mucosa and the central nervous

    system. In adulthood, Ireb2–/– mice develop a movement

    disorder characterized by ataxia, bradykinesia and tremor. Significant

    accumulations of iron in white matter tracts and nuclei

    throughout the brain precede the onset of neurodegeneration

    and movement disorder symptoms by many months. Ferric iron

    accumulates in the cytosol of neurons and oligodendrocytes in

    distinctive regions of the brain.
    Abnormal accumulations of ferritin

    colocalize with iron accumulations in populations of neurons

    that degenerate, and iron-laden oligodendrocytes

    accumulate ubiquitin-positive inclusions. Thus, misregulation

    of iron metabolism leads to neurodegenerative disease in

    Ireb2–/– mice and may contribute to the pathogenesis of comparable

    human neurodegenerative diseases.
     
  3. Jack Kruse

    Jack Kruse Administrator

    Iron is dirty little bugger for us.......the more fruit we eat the more we absorb it. But it is tightly regulated by us unless our hormones are trashed and most humans are today.
     

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