HuR and mRNA stability

Brennan, Christopher M.; Steitz, Joan A.

doi:10.1007/pl00000854

Cited by 971 publications

(1,012 citation statements)

References 121 publications

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“…VEGF mRNA is extremely labile in normoxic conditions, with a half-life of less than 1 hour, as compared with the average halflife of 10 to 12 hours for eukaryotic mRNA. During hypoxia, the half-life of VEGF mRNA increases by two to three-fold (Levy et al, 1996) due to a stabilizing effect of HuR, a 36 kDa RNA-binding protein, which binds with high affinity to AREs in the 3′-UTR of VEGF mRNA, protecting it from degradation by endonucleases (Brennan and Steitz, 2001;Robinow et al, 1988).…”

Section: Regulation Of Vegf Expressionmentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

612

527

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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Section: Regulation Of Vegf Expressionmentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

612

527

View full text Add to dashboard Cite

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“…In mammals and in Xenopus, the Hu family consists of three members that are developmentally regulated and tissue-specific-Hel-N1 (also called HuB), HuC, and HuD-and one (HuR) that is ubiquitously expressed in all cell types (Szabo et al, 1991;King et al, 1994;Good, 1995;Ma et al, 1996;Antic and Keene, 1997). HuR is the best-characterized ELAV protein Brennan and Steitz, 2001;Wilusz et al, 2001). It has a high binding affinity for several AREs Good, 1997;Levy et al, 1998;Maurer et al, 1999;Sakai et al, 1999;Sokolowski et al, 1999), and although predominantly nuclear, it shuttles between the nucleus and the cytoplasm, affecting mRNA stability and translation (Fan and Steitz, 1998).…”

Section: Hurmentioning

confidence: 99%

Post‐transcriptional regulation of gene expression by degradation of messenger RNAs

Bevilacqua

Ceriani

Capaccioli

et al. 2003

Journal Cellular Physiology

293

259

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Recent evidence suggests that gene expression may be regulated, at least in part, at post-transcriptional level by factors inducing the extremely rapid degradation of messenger RNAs. These factors include reactions between adenyl-uridyl-rich elements (AREs) of the relevant mRNA and either specific proteins that bind to these elements or exosomes. This review deals with examples of the proteins (AU-rich binding proteins, AUBPs) and exosomes, which have been shown to form complexes with AREs and bring about rapid degradation of the relevant mRNA, and with certain other factors, which protect the RNA from such degradation. The biochemical and physiological factors underlying the stability of messenger RNAs carrying the ARE motifs will be reviewed in the light of their emerging significance for cell physiology, human pathology, and molecular medicine. We also consider the possible application of the results of recent insights into the mechanisms to pharmacological interventions to prevent or cure disorders, especially developmental disorders, which the suppression of gene expression may bring about. Molecular targeting of specific steps in protein degradation by synthetic compounds has already been utilized for the development of pharmacological therapies.

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“…The subsequent analysis of the CD83 transcript revealed that this mRNA contains in its coding region, a highly structured cis-active RNA sequence, termed the post-transcriptional regulatory element (PRE), and that this RNA element is directly recognized by the cellular RNA-binding shuttle protein HuR [32]. Interestingly, PRE:HuR interaction does not affect, as it was shown with other HuR targets such as early response gene mRNA [33], the stability of this transcript. Instead, this interaction induces the CRM1-dependent cytoplasmic accumulation of CD83 mRNA [32].…”

mentioning

confidence: 94%

Phosphorylation of the HuR ligand APRIL by casein kinase 2 regulates CD83 expression

et al. 2009

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Fully mature DC and, to a lesser extent, activated T and B cells express CD83, a surface molecule that appears to fulfil an important role in efficient T-cell activation. Recently, it has been shown that CD83 mRNA is transported from the nucleus to the cytoplasm by an uncommon route, involving the cellular RNA-binding protein HuR and the nuclear export receptor CRM1. Moreover, the shuttle phosphoprotein APRIL (ANP32B) has been shown to be required for HuR-mediated nucleocytoplasmic translocation of the CD83 mRNA by acting as an adaptor that links HuR and CRM1. Here, we are able to report that casein kinase 2 (CK2) phosphorylates APRIL on residue threonine244 (Thr 244 ) and demonstrate that the CK2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes CD83 expression in activated Jurkat T cells by interfering with the nucleocytoplasmic translocation of CD83 mRNA. Depletion and knockdown studies demonstrate that the CK2 a 0 subunit is necessary for this regulation, whereas the CK2 a subunit seems to be dispensable. Taken together, the data presented significantly extend our knowledge of the complex regulation of CD83 mRNA processing and provides a novel strategy to interfere with CD83 expression.Key words: APRIL . Casein kinase 2 . CD83 . HuR . Leukocytes IntroductionMature DC are capable of sensitizing even naïve CD4 1 and CD8 1 T cells, and are therefore frequently termed ''nature's adjuvant''. Immature DC reside in the peripheral tissues and upon uptake of antigen and exposure to inflammatory stimuli, they migrate to the peripheral lymph nodes, where now fully matured, they induce antigen-specific T-cell response [1][2][3][4]. The DC maturation process includes the modulation of chemokine and chemokine receptors, as well as the up-regulation of several cytokines, costimulatory and adhesion molecules [5].Human CD83 serves as a major marker molecule for mature DC that belongs to the immunoglobulin super family [6,7]. This membrane-bound protein is also expressed, although to a significant lower extent, on activated T and B cells [7][8][9][10]. Moreover, a soluble form of CD83 is detectable at low levels in sera derived from healthy individuals, whereas in contrast, elevated levels are present in patients suffering from certain hematological malignancies [8,11]. Notwithstanding the fact that accumulating experimental evidence suggests that CD83 plays an important functional role in the regulation of DCmediated T-cell-specific immune response [12][13][14][15][16][17][18][19], the exact function of CD83 remains poorly understood [20][21][22]. Nevertheless, various disease-related findings suggest that CD83 holds great potential for future therapeutic application [23]. For example, EAE can be prevented in mice by applying a soluble form of CD83 [24]. Likewise, in rats, a positive therapeutic effect on experimental autoimmune myasthenia gravis has been reported by application of pentoxifylline, a drug that apparently interferes with CD83 expression [25,26]. Furthermore, CD83 1 DC were found to localize i...

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HuR and mRNA stability

Cited by 971 publications

References 121 publications

Vascular endothelial growth factor in eye disease

Vascular endothelial growth factor in eye disease

Post‐transcriptional regulation of gene expression by degradation of messenger RNAs

Phosphorylation of the HuR ligand APRIL by casein kinase 2 regulates CD83 expression

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