Disease relevance of ELAVL1

• Altered expression of the mRNA stability factor HuR promotes cyclooxygenase-2 expression in colon cancer cells [1].
• Within the glioblastoma multiforme, prominent HuR expression was also detected in perinecrotic areas in which angiogenic growth factors are up-regulated [2].
• To further define its role as a potential RNA stabilizer, we analyzed whether HuR could bind to the stability motifs within the 3'-UTRs of cytokines and growth factors linked to brain tumor progression [2].
• Using a novel HuR-specific polyclonal antibody, we found that strong HuR protein expression was limited to high-grade malignancies (glioblastoma multiforme and medulloblastoma) [2].
• Role of elongin-binding domain of von Hippel Lindau gene product on HuR-mediated VPF/VEGF mRNA stability in renal cell carcinoma [3].

High impact information on ELAVL1

• The derepression requires binding of HuR, an AU-rich-element binding protein, to the 3'UTR of CAT-1 mRNA [4].
• HuD, a paraneoplastic encephalomyelitis antigen, contains RNA-binding domains and is homologous to Elav and Sex-lethal [5].
• Consistent with an inhibitory role of Hu proteins in p27 translation, siRNA mediated knockdown of HuR induced endogenous p27 protein levels as well as IRES-mediated reporter translation and leads to cell cycle arrest in G1 [6].
• The approximately 30-kD ELAV protein HuR specifically bound to RNAs containing an AU-rich element derived from the TNF-alpha mRNA in the in vitro system [7].
• These data suggest that mammalian ELAV proteins play a role in regulating mRNA stability by influencing the access of degradative enzymes to RNA substrates [7].

Chemical compound and disease context of ELAVL1

• HuR, a RNA stability factor, is expressed in malignant brain tumors and binds to adenine- and uridine-rich elements within the 3' untranslated regions of cytokine and angiogenic factor mRNAs [2].
• In ovarian cancer cells in vitro, a small interfering RNA against HuR and leptomycin B, an inhibitor of nucleocytoplasmic translocation of HuR, inhibited COX-2 expression [8].
• Tumor necrosis factor alpha induces angiogenic factor up-regulation in malignant glioma cells: a role for RNA stabilization and HuR [9].
• In the balloon injured rabbit aorta model, systemic inflammation induced by LPS caused intimal hyperplasia and increased TLR4 and HuR expression [10].

Biological context of ELAVL1

• Upon decreasing HADHB mRNA with RNA interference, renin protein and mRNA stability increased, whereas RNA interference against HuR caused these to decrease [11].
• Antibodies against a methylated HuR peptide were used to demonstrate in vivo methylation of HuR [12].
• The mechanism by which these stimuli activate HuR is unclear and might be related to post-translational modification of this protein [12].
• Thus, CARM1, which plays a role in transcriptional activation through histone H3 methylation, may also play a role in post-transcriptional gene regulation by methylating HuR [12].
• Transportins 1 and 2 are redundant nuclear import factors for hnRNP A1 and HuR [13].

Anatomical context of ELAVL1

• Importantly, lipopolysaccharide stimulation of macrophages, which leads to HuR-mediated stabilization of tumor necrosis factor alpha mRNA in these cells, caused increased methylation of endogenous HuR [12].
• Intracellular imaging revealed distinct localization of HADHB to mitochondria, HuR to nuclei, and CP1 throughout the cell [11].
• In digitonin-permeabilized HeLa cells, both M9 and HNS peptides compete for the import of recombinant hnRNP A1 and HuR, indicating that HuR and hnRNP A1 import pathways are at least partially overlapping [13].
• All cell lines showed an expression of HuR mRNA and protein [14].
• Finally, we show that HuR overexpression in HL-60 cells significantly increases the SLC11A1 mRNA stability [15].

Associations of ELAVL1 with chemical compounds

• Here we show that HuR can be methylated on arginine [12].
• Binding of neuronal ELAV-like proteins to the uridine-rich sequence in the 3'-untranslated region of tumor necrosis factor-alpha messenger RNA [16].
• The present study also showed that the substitutions of glutamic acid at 42 for aspartic acid and leucine at 44 for phenylalanine in the first potent alpha-helix structure of RRM1, as were seen in another ELAV-like protein Hel-N1, markedly affected the RNA binding [17].
• We have shown that the h1ARE interacts with heterogeneous nuclear ribonucleoprotein (hnRNP) C1/C2 and the ELAV-like HuR protein [18].
• The inhibition of CRM1 by leptomycin B leads to the nuclear retention of pp32 and APRIL, their increased association with HuR, and an increase in HuR's association with nuclear poly(A)+ RNA [19].
• Treatment with the MAP kinase activator, anisomycin, which commonly stabilizes ARE-containing mRNAs, caused rapid nuclear to cytoplasmic shuttling of HuR [20].

Physical interactions of ELAVL1

• Novel binding of HuR and poly(C)-binding protein to a conserved UC-rich motif within the 3'-untranslated region of the androgen receptor messenger RNA [21].
• While the cross-linking patterns were similar, quantitative immunoprecipitation of native IL-8 RNA from IL-1beta-stimulated cytoplasmic extract revealed a 20-fold greater association of transcript with the stabilizing factor HuR vs. the destabilizing factor KSRP [22].
• In this study, we showed that a human neuronal ELAV-like protein binds to the ARE in the 3'-UTR of TNF-alpha mRNA [16].
• Cell culture studies have shown that the mRNA of cyclooxygenase (COX)-2 can be stabilized by HuR [23].
• Here we analyze the expression of SLC11A1 in human monocytes and HL-60 cells and then use HL-60 cells as a model to determine whether RNA-binding protein HuR is associated with the ARE and involved in SLC11A1 mRNA turnover [15].
• RNA pull-down assay and RNA electrophoretic mobility shift assay demonstrated that the HuR shuttling by ATP is accompanied by an increased HuR binding to cyclooxygenase (COX)-2 mRNA [24].

Co-localisations of ELAVL1

• Double-labeling immunofluorescence showed that VEGF protein colocalizes with HuR in discrete nuclear compartments and nuclear VEGF protein was increased in hypoxia [25].
• Here we show that heat shock induces increased association of HuR with pp32 and APRIL through protein-protein interactions and that these ligands partially colocalize with HuR in cytoplasmic foci [26].

Enzymatic interactions of ELAVL1

• Our findings suggest that Cdk1 phosphorylates HuR during G2, thereby helping to retain it in the nucleus in association with 14-3-3 and hindering its post-transcriptional function and anti-apoptotic influence [27].

Regulatory relationships of ELAVL1

• Suppression of HuR expression by RNA interference partially blocked the accumulation of ATF3 mRNA following amino acid deprivation [28].
• HuR regulates p21 mRNA stabilization by UV light [29].
• Stabilization of urokinase and urokinase receptor mRNAs by HuR is linked to its cytoplasmic accumulation induced by activated mitogen-activated protein kinase-activated protein kinase 2 [30].
• Androgen treatment also changes the amount of HuR-protected riboprobe pulled down from a PC-3 clone expressing a functional androgen receptor [31].
• In vitro, HuR enhanced whereas CUGBP2 inhibited translation of the chimeric luciferase COX-2 3'UTR mRNA [32].

Other interactions of ELAVL1

• Influence of the RNA-binding protein HuR in pVHL-regulated p53 expression in renal carcinoma cells [33].
• In keeping with earlier reports, the elevated cytoplasmic HuR in VHL(+) cells was likely due to the reduced AMP-activated kinase activity in these cells [33].
• HuR methylation increased in cells that overexpressed CARM1 [12].
• However, HuR is not a substrate for PRMT1, the most prominent protein-arginine methyltransferase in mammalian cells, which methylates a number of heterogeneous nuclear ribonucleoproteins [12].
• Expression of the ELAV-like protein HuR is associated with higher tumor grade and increased cyclooxygenase-2 expression in human breast carcinoma [23].

Analytical, diagnostic and therapeutic context of ELAVL1

• EXPERIMENTAL DESIGN: To investigate a possible contribution of dysregulation of mRNA stability to the progression of cancer and to overexpression of COX-2, we studied expression of HuR in 208 primary breast carcinomas by immunohistochemistry [23].
• 2. This localization was confirmed by radiation hybrid mapping and coincides with that of HuR (HGMW-approved symbol ELAVL1), another elav family member [34].
• In order to investigate this possibility we have mapped the HuR gene using fluorescence in-situ hybridization (FISH) [35].
• Thus, while the genomic organization of mHuA is similar to the neural-restricted members of the Elav family, the promoter element differs substantially both by sequence analysis and transcriptional activity in non-neural cell types [36].
• Here, HuR was immunoprecipitated under conditions that preserved HuR-RNA interactions, and HuR-bound target mRNAs were identified by cDNA array hybridization [37].

References