Thyrotropin-releasing Hormone and Epidermal Growth Factor Regulate Iron-regulatory Protein Binding in Pituitary Cells via Protein Kinase C-dependent and -independent Signaling Pathways

Thomson, A. D.; Rogers, Jack T.; Leedman, Peter J.

doi:10.1074/jbc.m002354200

Cited by 38 publications

(33 citation statements)

References 70 publications

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“…. In fact, it has been reported that hormonal signals may regulate post-transcriptionally the synthesis of proteins involved in iron metabolism by affecting IRPs ability to bind to IRE, possibly through induction of signal transduction cascades that result in IRPs phosphorylation [25,47]. In adipose tissue estrogen may also have rapid, non-genomic biological effects, believed to be mediated through a small fraction of estrogen receptors localized at or near the cell membrane [45].…”

Section: Discussionmentioning

confidence: 99%

Ovariectomy and estrogen treatment modulate iron metabolism in rat adipose tissue

Raso

Irace

Esposito

et al. 2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 30A c c e p t e d M a n u s c r i p Graphical AbstractPage 2 of 30 A c c e p t e d M a n u s c r i p t E-mail address: rsantama@unina.it (R. Santamaria). * ManuscriptPage 3 of 30 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 ABSTRACTIron is essential for many biological processes and its deficiency or excess is involved in pathological conditions. At cellular level, the maintenance of iron homeostasis is largely accomplished by the transferrin receptor (TfR)-1 and by ferritin, whose expression is mainly regulated post-transcriptionally by Iron Regulatory Proteins (IRPs).This study examines the hypothesis that modification of serum estrogen levels by ovariectomy and 17β-estradiol (E 2 ) treatment in rats modulate serum iron-status parameters and iron metabolism in adipose tissue. In particular, we evaluated the RNA binding of IRP1 by electrophoretic mobility shift assay and IRP1, ferritin, and TfR-1 expression in adipose tissue by Western blot analysis.Ovariectomy, besides a lowered serum iron and transferrin iron binding capacity, remarkably decreased the binding activity of IRP1 in peritoneal and subcutaneous adipose tissues, and these effects were reversed by E 2 treatment. Moreover, ovariectomy determined a decrease of IRP1 expression, which was significant in subcutaneous adipose tissue. Consistent with IRP1 regulation, an increase of ferritin and a decrease of TfR-1 expression were observed in peritoneal adipose tissue from ovariectomized animals, while the treatment with E 2 reconstituted TfR-1 level. A similar expression profile of TfR-1 was observed in subcutaneous adipose tissue, where ferritin level did not change in ovariectomized animals, and was increased after E 2 treatment.Our results indicate that estrogen level changes can regulate the binding activity of the IRP1, and consequently ferritin and TfR-1 expression in adipose tissue, suggesting a relationship among serum and tissue iron parameters, estrogen status and adiposity.

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Section: Discussionmentioning

confidence: 99%

Ovariectomy and estrogen treatment modulate iron metabolism in rat adipose tissue

Raso

Irace

Esposito

et al. 2009

Biochemical Pharmacology

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“…Cell Culture-Human hepatoma HepG2 (ATCC HB-8065) and Hep3B (ATCC HB-8064) cells were grown in Dulbecco's minimal essential medium (Invitrogen) supplemented with 10% fetal bovine serum, L-glutamine, essential amino acids, penicillin, and streptomycin (Invitrogen) (7).…”

Section: Methodsmentioning

confidence: 99%

“…Cytoplasmic Protein Extracts-Cytoplasmic protein extracts of treated HepG2 cell cultures were prepared as described (7). Briefly, cells were scraped from culture dishes in chilled phosphate-buffered saline, centrifuged at 450 ϫ g for 4 min at 4°C, washed again in phosphate-buffered saline, and then incubated for 20 min in cold cytoplasmic extraction buffer (10 mM HEPES, 3 M MgCl 2 , 40 mM KCl, 5% glycerol, 0.2% Nonidet P-40, 1 mM dithiothreitol) containing freshly added protease inhibitors (0.5 mM phenylmethylsulfonyl fluoride, 10 g/ml leupeptin, 2 g/ml aprotinin).…”

Section: Methodsmentioning

confidence: 99%

“…IP-RT-PCR Assay-HepG2 cells were grown (ϮFe 2 Tf (10 M) and ϮIL-1␤ (1 ng/ml)), and cytoplasmic extracts were harvested in cytoplasmic extraction buffer as described (7). Cytoplasmic extract (200 g) was added to 10 g of ␣CP1 or ␣CP2 antibody (Ab).…”

Section: Interleukin-1 Control Of H-ferritin Translationmentioning

confidence: 99%

“…Iron and oxidative stress are known to modulate the first stage of translation of ferritin mRNAs when the 43 S ribosome subunit attaches to the 5Ј cap-specific M 7 GpppN in the 5Ј-UTR 1 of L-and H-ferritin mRNAs (1)(2)(3)(4). The iron regulatory proteins (IRP1 and IRP2, iso-IRPs) play a central role in regulating ferritin mRNA translation.…”

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The Acute Box cis-Element in Human Heavy Ferritin mRNA 5′-Untranslated Region Is a Unique Translation Enhancer That Binds Poly(C)-binding Proteins

Thomson

Cahill

Cho

et al. 2005

Journal of Biological Chemistry

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Intracellular levels of the light (L) and heavy (H) ferritin subunits are regulated by iron at the level of message translation via a modulated interaction between the iron regulatory proteins (IRP1 and IRP2) and a 5-untranslated region. Iron-responsive element (IRE). Here we show that iron and interleukin-1␤ (IL-1␤) act synergistically to increase H-and L-ferritin expression in hepatoma cells. A GC-rich cis-element, the acute box (AB), located downstream of the IRE in the H-ferritin mRNA 5-untranslated region, conferred a substantial increase in basal and IL-1␤-stimulated translation over a similar time course to the induction of endogenous ferritin. A scrambled version of the AB was unresponsive to IL-1. Targeted mutation of the AB altered translation; reverse orientation and a deletion of the AB abolished the wild-type stem-loop structure and abrogated translational enhancement, whereas a conservative structural mutant had little effect. Labeled AB transcripts formed specific complexes with hepatoma cell extracts that contained the poly(C)-binding proteins, iso-␣CP1 and -␣CP2, which have well defined roles as translation regulators. Iron influx increased the association of ␣CP1 with ferritin mRNA and decreased the ␣CP2-ferritin mRNA interaction, whereas IL-1␤ reduced the association of ␣CP1 and ␣CP2 with H-ferritin mRNA. In summary, the Hferritin mRNA AB is a key cis-acting translation enhancer that augments H-subunit expression in Hep3B and HepG2 hepatoma cells, in concert with the IRE. The regulated association of H-ferritin mRNA with the poly(C)-binding proteins suggests a novel role for these proteins in ferritin translation and iron homeostasis in human liver.The mechanisms governing the regulation of ferritin mRNA translation are complex, but their elucidation is critical to understanding iron homeostasis. Iron and oxidative stress are known to modulate the first stage of translation of ferritin mRNAs when the 43 S ribosome subunit attaches to the 5Ј cap-specific M 7 GpppN in the 5Ј-UTR 1 of L-and H-ferritin mRNAs (1-4). The iron regulatory proteins (IRP1 and IRP2, iso-IRPs) play a central role in regulating ferritin mRNA translation. During conditions of intracellular iron chelation with desferrioxamine (DesF) and oxidative stress, the IRPs bind with higher affinity to the conserved iron-response element (IRE) RNA stem loop 40 nucleotides (nt) downstream of the 5Ј cap sites of the L-and H-ferritin mRNAs (1). This translational repression event prevents attachment of the small ribosome subunit to the 5Ј cap sites of the L-and H-ferritin mRNAs and inhibits ferritin translation (2). In contrast, after iron influx the iso-IRPs are released from the 5Ј cap IREs, and ferritin translation is no longer inhibited, increasing the cellular iron storage capacity (2, 3). The IRP2 knock-out mouse, which is characterized by unregulated ferritin mRNA translation and ferritin accumulation in neurons and gut epithelial cells in a gene-dose manner, validated these observations in vivo (4). Recently zinc and cadmium were ...

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The androgen receptor mRNA

2004

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Androgens (testosterone), acting via the androgen receptor (AR) a nuclear transcription factor, regulate male sexual development and body composition. In addition, AR expression plays an important role in the proliferation of human prostate cancer and confers a better prognosis in breast cancer. AR mRNA stability is central to the regulation of AR expression in prostate and breast cancer cells, and recent studies have demonstrated binding by members of the ELAV/Hu and poly(C) RNA-binding protein families to a highly conserved UC-rich element in the 3'-untranslated region of AR mRNA, with functional impact on AR protein expression. Remarkably, a CAG trinucleotide repeat in exon 1 of the AR, the length of which has been linked to prostate cancer survival, is also a target for multiple RNA-binding proteins from a variety of human and murine tissues. In this review, we will detail the current knowledge of the mechanisms involved in regulating AR mRNA stability, the nature, potential role and structural biology of several novel AR mRNA-protein interactions, and the implications for novel therapeutics in human prostate cancer.

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Thyrotropin-releasing Hormone and Epidermal Growth Factor Regulate Iron-regulatory Protein Binding in Pituitary Cells via Protein Kinase C-dependent and -independent Signaling Pathways

Cited by 38 publications

References 70 publications

Ovariectomy and estrogen treatment modulate iron metabolism in rat adipose tissue

Ovariectomy and estrogen treatment modulate iron metabolism in rat adipose tissue

The Acute Box cis-Element in Human Heavy Ferritin mRNA 5′-Untranslated Region Is a Unique Translation Enhancer That Binds Poly(C)-binding Proteins

The androgen receptor mRNA

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