HADHB, HuR, and CP1 Bind to the Distal 3′-Untranslated Region of Human Renin mRNA and Differentially Modulate Renin Expression

Adams, David J.; Beveridge, Dianne J.; Weyden, Louise van der; Mangs, Helena; Leedman, Peter J.; Morris, Brian J.

doi:10.1074/jbc.m307782200

Cited by 58 publications

(63 citation statements)

References 73 publications

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“…16,24 For example, knockdown experiments for the protein HuR revealed that the half-life of human renin mRNA is decreased from 4.5 to 2.5 hours. 25 However, in addition to stabilization proteins, proteins that destabilize human renin mRNA were also found. So, the knockdown of HABHB revealed an increased half-life of the human renin mRNA to Ϸ12 hours.…”

Section: Discussionmentioning

confidence: 99%

Calcium Inhibits Renin Gene Expression by Transcriptional and Posttranscriptional Mechanisms

et al. 2005

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Abstract-The aim of this study was to investigate the role of cytosolic calcium for renin gene expression in juxtaglomerular cells. For this purpose, we used the immortalized juxtaglomerular mouse cell line As4.1. To increase cytosolic calcium concentration, we treated the cells with thapsigargin and cyclopiazonic acid, inhibitors of the endoplasmatic reticulum CaϪ ATPase. Thapsigargin and cyclopiazonic acid inhibited renin gene expression in a characteristic time and concentration-dependent manner. This effect was concentration-dependently blocked by BAPTA-AM, an intracellular Ca 2ϩ chelator. Pharmacological blocking of protein kinase C activity by calphostin, Gö6976, and Gö6983 did not change the effect of thapsigargin on renin gene expression. Experiments with renin1 C -promoter-reporter constructs revealed that thapsigargin inhibited renin gene transcription. Analysis of deletion constructs of the renin1 C promoter indicated that regulatory elements involved in the calcium-mediated inhibition of renin gene transcription are located in the enhancer region of the renin gene and that Ն3 transcription factor-binding sites are involved in this process. In addition, thapsigargin reduced the renin mRNA half-life from 10 hours (control conditions) to 4 hours. Knockdown studies with small interfering RNA directed to dynamin-1 mRNA revealed that dynamin-1 is likely to be involved in the calcium-mediated destabilization of renin mRNA. These data suggest that calcium inhibits renin gene expression in juxtaglomerular cells via a concerted action of inhibition of renin gene transcription and destabilization of renin mRNA. Key Words: calcium Ⅲ renin-angiotensin-aldosterone system Ⅲ thapsigargin Ⅲ mRNA stability T he renin-angiotensin-aldosterone system is a major regulatory system controlling extracellular fluid volume and blood pressure. The activity of the renin-angiotensin-aldosterone system is rate limited by the activity of the protease renin. 1 Renin itself is also regulated by a variety of factors. In the past few years, our knowledge has increased substantially about the regulation of renin gene expression at the cellular level. [2][3][4] For the transcription of the mouse renin gene, 2 critical regions, a proximal promoter region at Ϫ197 to Ϫ50 bp and an enhancer element at Ϫ2866 to Ϫ2625 bp, have been identified. 4 Also, the regulation of the renin mRNA stability is influenced by various factors, among these, interacting partner proteins like MINT, dynamin, or nucleolin have been found to be involved in the stabilization process of the renin mRNA. 5 The focus of our study was to investigate the role of calcium in the regulation of renin gene expression. This is of particular interest, because vasoactive peptides like angiotensin II or endothelin-1, which are known to be direct regulators of renin gene expression, activate the phospholipase C via a G protein-coupled receptor and, in turn, increase inositol triphosphate and diacylglycerol (DAG). 3 Whereas DAG is known to activate protein kinase C, inositol triphosp...

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Section: Discussionmentioning

confidence: 99%

Calcium Inhibits Renin Gene Expression by Transcriptional and Posttranscriptional Mechanisms

et al. 2005

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“…We have recently identified in vivo association of ␣CP1 with several transcripts including the human androgen receptor (18), p21 WAF1 (46), and renin (47). In the latter, ␣CP1 plays an important role in regulating the stability of renin mRNA.…”

Section: Discussionmentioning

confidence: 99%

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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“…In a collaboration with Peter Leedman at the University of Western Australia, David and Louise showed how human renin mRNA stability is controlled ( Figure 4A). 66 We identified an adenosine-cytosine (AU)-rich stem-loop sequence in the distal 3Ј-untranslated region (UTR) that serves as an instability element ( Figure 4C). More than 1 dozen cellular proteins bound to the 3Ј-UTR in vivo.…”

Section: Posttranscriptional Control Of Renin Gene Expressionmentioning

confidence: 99%

“…HADHB was enriched within juxtaglomerular cells, whereas the others were distributed throughout the kidney. 66 We suggested that by binding to the AU-rich region, HADHB recruits the degradation machinery of the cell to destroy renin mRNA ( Figure 4C). …”

Section: Posttranscriptional Control Of Renin Gene Expressionmentioning

confidence: 99%

Renin, Genes, and Beyond

Morris

2011

Hypertension

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HADHB, HuR, and CP1 Bind to the Distal 3′-Untranslated Region of Human Renin mRNA and Differentially Modulate Renin Expression

Cited by 58 publications

References 73 publications

Calcium Inhibits Renin Gene Expression by Transcriptional and Posttranscriptional Mechanisms

Calcium Inhibits Renin Gene Expression by Transcriptional and Posttranscriptional Mechanisms

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

Renin, Genes, and Beyond

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