HGNC Approved Gene Symbol:ELAVL1
Cytogenetic location:19p13.2 Genomic coordinates(GRCh38) :19:7,958,573-8,005,641 (from NCBI)
Cis-acting AU-rich elements (AREs) destabilize mRNAs and play an important role in the control of gene expression. Members of the ELAVL protein family, such as ELAVL1, contain 3 RNA-binding domains and bind to AREs (Ma et al., 1996).
By RT-PCR of HeLa cell mRNA using primers based on a conserved region of HuD (ELAVL4;168360),Ma et al. (1996) isolated a partial cDNA encoding ELAVL1, which they designated HuR. They recovered additional cDNAs corresponding to the entire coding region and determined that the predicted HuR protein contains 326 amino acids. Like other ELAVL proteins, HuR has a short N-terminal region followed by 2 RNA-binding motifs, a basic linker domain, and a third RNA-binding motif. RT-PCR analysis indicated that HuR was expressed ubiquitously, in contrast to the neural-specific expression of ELAVL2 (601673), ELAVL3 (603458), and ELAVL4.
Ma et al. (1996) found that recombinant HuR protein bound to AREs in both cytokine and oncogene mRNAs with high specificity and affinity.
Li et al. (2002) found that mammalian Carm1 (603934) associated with HuR and activated HuR via methylation in vitro and in vivo. Carm1 methylated HuR predominantly on arg217 in the hinge region between the second and third recognition motif domains. HuR methylation increased in cells that overexpressed Carm1, and lipopolysaccharide stimulation of mouse macrophages caused increased methylation of endogenous HuR, leading to the stabilization of TNF-alpha (TNF;191160) mRNA.
Bhattacharyya et al. (2006) found that endogenous cationic amino acid transporter-1 (CAT1, or SLC7A1;104615) mRNA was translationally repressed by miR122 (MIR122A;609582) in Huh7 human hepatoma cells. CAT1 mRNA and reporters bearing its 3-prime UTR could be relieved from miR122-mediated repression by subjecting Huh7 cells to different stress conditions. This derepression was accompanied by release of CAT1 mRNA from cytoplasmic processing bodies and its entry into polysomes, and this process involved binding of HuR to the 3-prime UTR of CAT1.
Abdelmohsen et al. (2007) showed that the 3-prime UTR of SIRT1 (604479) transcripts contains AREs with HuR binding motifs. They found that HuR associated with SIRT1 mRNA and enhanced its stability. In human diploid fibroblasts, they found a concomitant reduction in both HuR and SIRT1 during replicative senescence. Oxidative stress lowered SIRT1 mRNA and protein levels, caused the dissociation of HuR from SIRT1 mRNA, and reduced the stability of SIRT1 mRNA in an HuR-dependent manner. The oxidant-activated cell cycle checkpoint kinase CHK2 (CHEK2;604373) phosphorylated HuR and altered its binding to SIRT1 and other HuR target mRNAs.
Nucleolin (NCL;164035) functions in the nucleolus to regulate ribosomal RNA maturation and processing and in the cytoplasm to regulate mRNA stabilization and translation.Tominaga et al. (2011) found that HuR and microRNA-494 (MIR494;616036) competed for binding to the 3-prime UTR of the NCL transcript in HeLa cells. MIR494 inhibited NCL translation by targeting NCL to RNA processing bodies. Conversely, HuR promoted NCL translation by targeting the transcript to polysomes. Neither regulator altered NCL mRNA content.
By database analysis,Priyanka et al. (2021) showed that the long noncoding RNA HMS (LINC02381;620723) was upregulated in many cancer types, including lung cancer. Knockdown of HMS resulted in cell cycle arrest at G1 phase and reduced migration and invasiveness of cancer cells. In contrast, HMS overexpression enhanced proliferation, mutation, and invasiveness of cancer cells. Depletion of HMS resulted in decreased expression of HOXC10 (605560). The RNA-binding protein HuR mediated stability of the HOXC10 transcript via the HOXC10 3-prime UTR. HuR interacted specifically with the cytosine-rich stretches of HMS, which recruited HuR to the 3-prime UTR of HOXC10, thereby facilitating HOXC10 mRNA stabilization. Database analysis revealed a positive correlation between HOXC10 and HMS expression in human cancer, suggesting that HMS functioning as a HOXC10 mRNA-stabilizing factor might play an essential role in cancer.
By fluorescence in situ hybridization,Ma and Furneaux (1997) mapped the HuR gene to 19p13.2.
Katsanou et al. (2005) studied the role of HuR in inflammatory responses using a transgenic murine system in which overexpression of HuR was restricted to the myeloid lineage and was quantitatively regulated with tetracycline analogs. They found that HuR suppressed biosynthesis of specific inflammatory mediators (e.g., TNF;191160) in synergy with negative posttranscriptional modulators such as TIA1 (603518).Katsanou et al. (2005) proposed that the HuR/TIA1 cooperation results in the formation of an 'inert' reservoir of mRNAs that may subsequently become labile for degradation by tristetraprolin (ZFP36;190700).
Chi et al. (2011) stated that knockout of Hur in mice is embryonic lethal due to defective placental branching. They targeted Hur deletion to primordial germ cells and found that Hur deletion resulted in male, but not female, infertility. Histologic examination of Hur -/- testis revealed vacuolization of seminiferous tubules, extensive cell death during meiotic divisions, and failure of spermatid elongation. Overexpression of Hur also caused failure of spermatid elongation. Both deletion and overexpression of Hur led to downregulation and mislocalization of Hspa2 (140560), a critical regulator of spermatogenesis. RNA immunoprecipitation analysis of wildtype testis suggested that Hur bound Hspa2 mRNA.Chi et al. (2011) concluded that HUR is not essential for progenitor germ cell survival, but that it is required for completion of meiosis. They proposed that HUR may direct HSPA2 mRNA to polysomes and control HSPA2 expression at the translational level.
Sun et al. (2018) generated neuron-specific HuR-deficient mice of both sexes. Mutant mice developed poor motor skills, abnormal gait, and weak forelimb muscle strength, with no significant difference between male and female mice. Further analysis showed significant apoptotic loss of cortical and spinal motor neurons in HuR-deficient mice. Consistent with this observation, immunostaining showed that HuR-deficient neurons had increased levels of cleaved caspase-3 (CASP3;600636), a hallmark of cell apoptosis. Genomewide microarray analysis of brain tissue from mutant mice identified 3,516 genes that exhibited significantly altered expression compared with control mice, with an enrichment for genes related to negative regulation of cell growth. Further analysis showed that mutant mice displayed a molecular signature reminiscent of amyotrophic lateral sclerosis (ALS; see105400). In addition, HuR deficiency caused redistribution of Tdp43 (TARDBP;605078), to cytosolic granules, which has been linked to motor neuron disease.
Abdelmohsen, K., Pullmann, R., Jr., Lal, A., Kim, H. H., Galban, S., Yang, X., Blethrow, J. D., Walker, M., Shubert, J., Gillespie, D. A., Furneaux, H., Gorospe, M.Phosphorylation of HuR by Chk2 regulates SIRT1 expression. Molec. Cell 25: 543-557, 2007. [PubMed:17317627,images,related citations] [Full Text]
Bhattacharyya, S. N., Habermacher, R., Martine, U., Closs, E. I., Filipowicz, W.Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell 125: 1111-1124, 2006. [PubMed:16777601,related citations] [Full Text]
Chi, M. N., Auriol, J., Jegou, B., Kontoyiannis, D. L., Turner, J. M. A., de Rooij, D. G., Morello, D.The RNA-binding protein ELAVL1/HuR is essential for mouse spermatogenesis, acting both at meiotic and postmeiotic stages. Molec. Biol. Cell 22: 2875-2885, 2011. [PubMed:21737689,images,related citations] [Full Text]
Katsanou, V., Papadaki, O., Milatos, S., Blackshear, P. J., Anderson, P., Kollias, G., Kontoyiannis, D. L.HuR as a negative posttranscriptional modulator in inflammation. Molec. Cell 19: 777-789, 2005. [PubMed:16168373,related citations] [Full Text]
Li, H., Park, S., Kilburn, B., Jelinek, M. A., Henschen-Edman, A., Aswad, D. W., Stallcup, M. R., Laird-Offringa, I. A.Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1. J. Biol. Chem. 277: 44623-44630, 2002. [PubMed:12237300,related citations] [Full Text]
Ma, W.-J., Cheng, S., Campbell, C., Wright, A., Furneaux, H.Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein. J. Biol. Chem. 271: 8144-8151, 1996. [PubMed:8626503,related citations] [Full Text]
Ma, W.-J., Furneaux, H.Localization of the human HuR gene to chromosome 19p13.2. Hum. Genet. 99: 32-33, 1997. [PubMed:9003489,related citations] [Full Text]
Priyanka, P., Sharma, M., Das, S., Saxena, S.The lncRNA HMS recruits RNA-binding protein HuR to stabilize the 3'-UTR of HOXC10 mRNA. J. Biol. Chem. 297: 100997, 2021. [PubMed:34302808,images,related citations] [Full Text]
Sun, K., Li, X., Chen, X., Bai, Y., Zhou, G., Kokio-Cochran, O. N., Lamb, B., Hamilton, T. A., Lin, C.-Y., Lee, Y.-S., Herjan, T.Neuron-specific HuR-deficient mice spontaneously develop motor neuron disease. J. Immun. 201: 157-166, 2018. Note: Erratum: J. Immun. 201: 1600, 2018. Electronic Article. [PubMed:29760195,images,related citations] [Full Text]
Tominaga, K., Srikantan, S., Lee, E. K., Subaran, S. S., Martindale, J. L., Abdelmohsen, K., Gorospe, M.Competitive regulation of nucleolin expression by HuR and miR-494. Molec. Cell. Biol. 31: 4219-4231, 2011. [PubMed:21859890,images,related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: ELAVL1
Cytogenetic location: 19p13.2 Genomic coordinates(GRCh38) : 19:7,958,573-8,005,641(from NCBI)
Cis-acting AU-rich elements (AREs) destabilize mRNAs and play an important role in the control of gene expression. Members of the ELAVL protein family, such as ELAVL1, contain 3 RNA-binding domains and bind to AREs (Ma et al., 1996).
By RT-PCR of HeLa cell mRNA using primers based on a conserved region of HuD (ELAVL4; 168360), Ma et al. (1996) isolated a partial cDNA encoding ELAVL1, which they designated HuR. They recovered additional cDNAs corresponding to the entire coding region and determined that the predicted HuR protein contains 326 amino acids. Like other ELAVL proteins, HuR has a short N-terminal region followed by 2 RNA-binding motifs, a basic linker domain, and a third RNA-binding motif. RT-PCR analysis indicated that HuR was expressed ubiquitously, in contrast to the neural-specific expression of ELAVL2 (601673), ELAVL3 (603458), and ELAVL4.
Ma et al. (1996) found that recombinant HuR protein bound to AREs in both cytokine and oncogene mRNAs with high specificity and affinity.
Li et al. (2002) found that mammalian Carm1 (603934) associated with HuR and activated HuR via methylation in vitro and in vivo. Carm1 methylated HuR predominantly on arg217 in the hinge region between the second and third recognition motif domains. HuR methylation increased in cells that overexpressed Carm1, and lipopolysaccharide stimulation of mouse macrophages caused increased methylation of endogenous HuR, leading to the stabilization of TNF-alpha (TNF; 191160) mRNA.
Bhattacharyya et al. (2006) found that endogenous cationic amino acid transporter-1 (CAT1, or SLC7A1; 104615) mRNA was translationally repressed by miR122 (MIR122A; 609582) in Huh7 human hepatoma cells. CAT1 mRNA and reporters bearing its 3-prime UTR could be relieved from miR122-mediated repression by subjecting Huh7 cells to different stress conditions. This derepression was accompanied by release of CAT1 mRNA from cytoplasmic processing bodies and its entry into polysomes, and this process involved binding of HuR to the 3-prime UTR of CAT1.
Abdelmohsen et al. (2007) showed that the 3-prime UTR of SIRT1 (604479) transcripts contains AREs with HuR binding motifs. They found that HuR associated with SIRT1 mRNA and enhanced its stability. In human diploid fibroblasts, they found a concomitant reduction in both HuR and SIRT1 during replicative senescence. Oxidative stress lowered SIRT1 mRNA and protein levels, caused the dissociation of HuR from SIRT1 mRNA, and reduced the stability of SIRT1 mRNA in an HuR-dependent manner. The oxidant-activated cell cycle checkpoint kinase CHK2 (CHEK2; 604373) phosphorylated HuR and altered its binding to SIRT1 and other HuR target mRNAs.
Nucleolin (NCL; 164035) functions in the nucleolus to regulate ribosomal RNA maturation and processing and in the cytoplasm to regulate mRNA stabilization and translation. Tominaga et al. (2011) found that HuR and microRNA-494 (MIR494; 616036) competed for binding to the 3-prime UTR of the NCL transcript in HeLa cells. MIR494 inhibited NCL translation by targeting NCL to RNA processing bodies. Conversely, HuR promoted NCL translation by targeting the transcript to polysomes. Neither regulator altered NCL mRNA content.
By database analysis, Priyanka et al. (2021) showed that the long noncoding RNA HMS (LINC02381; 620723) was upregulated in many cancer types, including lung cancer. Knockdown of HMS resulted in cell cycle arrest at G1 phase and reduced migration and invasiveness of cancer cells. In contrast, HMS overexpression enhanced proliferation, mutation, and invasiveness of cancer cells. Depletion of HMS resulted in decreased expression of HOXC10 (605560). The RNA-binding protein HuR mediated stability of the HOXC10 transcript via the HOXC10 3-prime UTR. HuR interacted specifically with the cytosine-rich stretches of HMS, which recruited HuR to the 3-prime UTR of HOXC10, thereby facilitating HOXC10 mRNA stabilization. Database analysis revealed a positive correlation between HOXC10 and HMS expression in human cancer, suggesting that HMS functioning as a HOXC10 mRNA-stabilizing factor might play an essential role in cancer.
By fluorescence in situ hybridization, Ma and Furneaux (1997) mapped the HuR gene to 19p13.2.
Katsanou et al. (2005) studied the role of HuR in inflammatory responses using a transgenic murine system in which overexpression of HuR was restricted to the myeloid lineage and was quantitatively regulated with tetracycline analogs. They found that HuR suppressed biosynthesis of specific inflammatory mediators (e.g., TNF; 191160) in synergy with negative posttranscriptional modulators such as TIA1 (603518). Katsanou et al. (2005) proposed that the HuR/TIA1 cooperation results in the formation of an 'inert' reservoir of mRNAs that may subsequently become labile for degradation by tristetraprolin (ZFP36; 190700).
Chi et al. (2011) stated that knockout of Hur in mice is embryonic lethal due to defective placental branching. They targeted Hur deletion to primordial germ cells and found that Hur deletion resulted in male, but not female, infertility. Histologic examination of Hur -/- testis revealed vacuolization of seminiferous tubules, extensive cell death during meiotic divisions, and failure of spermatid elongation. Overexpression of Hur also caused failure of spermatid elongation. Both deletion and overexpression of Hur led to downregulation and mislocalization of Hspa2 (140560), a critical regulator of spermatogenesis. RNA immunoprecipitation analysis of wildtype testis suggested that Hur bound Hspa2 mRNA. Chi et al. (2011) concluded that HUR is not essential for progenitor germ cell survival, but that it is required for completion of meiosis. They proposed that HUR may direct HSPA2 mRNA to polysomes and control HSPA2 expression at the translational level.
Sun et al. (2018) generated neuron-specific HuR-deficient mice of both sexes. Mutant mice developed poor motor skills, abnormal gait, and weak forelimb muscle strength, with no significant difference between male and female mice. Further analysis showed significant apoptotic loss of cortical and spinal motor neurons in HuR-deficient mice. Consistent with this observation, immunostaining showed that HuR-deficient neurons had increased levels of cleaved caspase-3 (CASP3; 600636), a hallmark of cell apoptosis. Genomewide microarray analysis of brain tissue from mutant mice identified 3,516 genes that exhibited significantly altered expression compared with control mice, with an enrichment for genes related to negative regulation of cell growth. Further analysis showed that mutant mice displayed a molecular signature reminiscent of amyotrophic lateral sclerosis (ALS; see 105400). In addition, HuR deficiency caused redistribution of Tdp43 (TARDBP; 605078), to cytosolic granules, which has been linked to motor neuron disease.
Abdelmohsen, K., Pullmann, R., Jr., Lal, A., Kim, H. H., Galban, S., Yang, X., Blethrow, J. D., Walker, M., Shubert, J., Gillespie, D. A., Furneaux, H., Gorospe, M.Phosphorylation of HuR by Chk2 regulates SIRT1 expression. Molec. Cell 25: 543-557, 2007. [PubMed: 17317627] [Full Text: https://doi.org/10.1016/j.molcel.2007.01.011]
Bhattacharyya, S. N., Habermacher, R., Martine, U., Closs, E. I., Filipowicz, W.Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell 125: 1111-1124, 2006. [PubMed: 16777601] [Full Text: https://doi.org/10.1016/j.cell.2006.04.031]
Chi, M. N., Auriol, J., Jegou, B., Kontoyiannis, D. L., Turner, J. M. A., de Rooij, D. G., Morello, D.The RNA-binding protein ELAVL1/HuR is essential for mouse spermatogenesis, acting both at meiotic and postmeiotic stages. Molec. Biol. Cell 22: 2875-2885, 2011. [PubMed: 21737689] [Full Text: https://doi.org/10.1091/mbc.E11-03-0212]
Katsanou, V., Papadaki, O., Milatos, S., Blackshear, P. J., Anderson, P., Kollias, G., Kontoyiannis, D. L.HuR as a negative posttranscriptional modulator in inflammation. Molec. Cell 19: 777-789, 2005. [PubMed: 16168373] [Full Text: https://doi.org/10.1016/j.molcel.2005.08.007]
Li, H., Park, S., Kilburn, B., Jelinek, M. A., Henschen-Edman, A., Aswad, D. W., Stallcup, M. R., Laird-Offringa, I. A.Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1. J. Biol. Chem. 277: 44623-44630, 2002. [PubMed: 12237300] [Full Text: https://doi.org/10.1074/jbc.M206187200]
Ma, W.-J., Cheng, S., Campbell, C., Wright, A., Furneaux, H.Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein. J. Biol. Chem. 271: 8144-8151, 1996. [PubMed: 8626503] [Full Text: https://doi.org/10.1074/jbc.271.14.8144]
Ma, W.-J., Furneaux, H.Localization of the human HuR gene to chromosome 19p13.2. Hum. Genet. 99: 32-33, 1997. [PubMed: 9003489] [Full Text: https://doi.org/10.1007/s004390050305]
Priyanka, P., Sharma, M., Das, S., Saxena, S.The lncRNA HMS recruits RNA-binding protein HuR to stabilize the 3'-UTR of HOXC10 mRNA. J. Biol. Chem. 297: 100997, 2021. [PubMed: 34302808] [Full Text: https://doi.org/10.1016/j.jbc.2021.100997]
Sun, K., Li, X., Chen, X., Bai, Y., Zhou, G., Kokio-Cochran, O. N., Lamb, B., Hamilton, T. A., Lin, C.-Y., Lee, Y.-S., Herjan, T.Neuron-specific HuR-deficient mice spontaneously develop motor neuron disease. J. Immun. 201: 157-166, 2018. Note: Erratum: J. Immun. 201: 1600, 2018. Electronic Article. [PubMed: 29760195] [Full Text: https://doi.org/10.4049/jimmunol.1701501]
Tominaga, K., Srikantan, S., Lee, E. K., Subaran, S. S., Martindale, J. L., Abdelmohsen, K., Gorospe, M.Competitive regulation of nucleolin expression by HuR and miR-494. Molec. Cell. Biol. 31: 4219-4231, 2011. [PubMed: 21859890] [Full Text: https://doi.org/10.1128/MCB.05955-11]
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