ELAV-like protein 1: Difference between revisions

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{{Infobox_gene}}
{{Infobox_gene}}
'''ELAV-like protein 1''' or '''HuR''' (human antigen R) is a [[protein]] that in humans is encoded by the ''ELAVL1'' [[gene]].<ref name="pmid8626503">{{cite journal | vauthors = Ma WJ, Cheng S, Campbell C, Wright A, Furneaux H | title = Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein | journal = J Biol Chem | volume = 271 | issue = 14 | pages = 8144–8151 |date=Jun 1996 | pmid = 8626503 | doi =10.1074/jbc.271.14.8144 | doi-access = free }}</ref><ref name="pmid9003489">{{cite journal | vauthors = Ma WJ, Furneaux H | title = Localization of the human HuR gene to chromosome 19p13.2 | journal = Hum Genet | volume = 99 | issue = 1 | pages = 32–33 |date=Feb 1997 | pmid = 9003489 | doi =10.1007/s004390050305 | s2cid = 32509747 }}</ref>
'''ELAV-like protein 1''' or '''HuR''' (human antigen R) is a [[protein]] that in humans is encoded by the ''ELAVL1'' [[gene]].<ref name="pmid8626503">{{cite journal | vauthors = Ma WJ, Cheng S, Campbell C, Wright A, Furneaux H | title = Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein | journal = Journal of Biological Chemistry | volume = 271 | issue = 14 | pages = 8144–8151 |date=Jun 1996 | pmid = 8626503 | doi =10.1074/jbc.271.14.8144 | doi-access = free }}</ref><ref name="pmid9003489">{{cite journal | vauthors = Ma WJ, Furneaux H | title = Localization of the human HuR gene to chromosome 19p13.2 | journal = Human Genetics | volume = 99 | issue = 1 | pages = 32–33 |date=Feb 1997 | pmid = 9003489 | doi =10.1007/s004390050305 | s2cid = 32509747 }}</ref>


The protein encoded by this gene is a member of the ELAVL protein family. This encoded protein contains 3 RNA-binding domains and binds cis-acting [[AU-rich element|AU-rich elements]] in [[3' untranslated region|3' untranslated regions]]. One of its best-known functions is to stabilize [[mRNA]]s in order to regulate gene expression.<ref>{{cite web | title = Entrez Gene: ELAVL1 ELAV (embryonic lethal, abnormal vision, Drosophila)-like 1 (Hu antigen R)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1994}}</ref> Various [[Post-translational modification|post-translational modifications]] of HuR influence its [[subcellular]] localization and stability of binding to mRNAs.<ref name=":0">{{Cite journal |last=Doller |first=Anke |last2=Pfeilschifter |first2=Josef |last3=Eberhardt |first3=Wolfgang |date=2008 |title=Signalling pathways regulating nucleo-cytoplasmic shuttling of the mRNA-binding protein HuR |url=https://pubmed.ncbi.nlm.nih.gov/18585896/ |journal=Cellular Signalling |volume=20 |issue=12 |pages=2165–2173 |doi=10.1016/j.cellsig.2008.05.007 |issn=1873-3913 |pmid=18585896}}</ref>
The protein encoded by this gene is a member of the ELAVL protein family. This encoded protein contains 3 RNA-binding domains and binds cis-acting [[AU-rich element|AU-rich elements]] in [[3' untranslated region|3' untranslated regions]]. One of its best-known functions is to stabilize [[mRNA]]s in order to regulate gene expression.<ref>{{cite web | title = Entrez Gene: ELAVL1 ELAV (embryonic lethal, abnormal vision, Drosophila)-like 1 (Hu antigen R)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1994}}</ref> Various [[Post-translational modification|post-translational modifications]] of HuR influence its [[subcellular]] localization and stability of binding to mRNAs.<ref name=":0">{{Cite journal |last=Doller |first=Anke |last2=Pfeilschifter |first2=Josef |last3=Eberhardt |first3=Wolfgang |date=2008 |title=Signalling pathways regulating nucleo-cytoplasmic shuttling of the mRNA-binding protein HuR |url=https://pubmed.ncbi.nlm.nih.gov/18585896/ |journal=Cellular Signalling |volume=20 |issue=12 |pages=2165–2173 |doi=10.1016/j.cellsig.2008.05.007 |issn=1873-3913 |pmid=18585896}}</ref>
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== Function ==
== Function ==
This RNA-binding protein has been found to be involved in a number of valuable cellular processes in mammals, including embryonic development, stress responses, and the immune system.<ref>{{Cite journal |last=Katsanou |first=Vicky |last2=Milatos |first2=Stavros |last3=Yiakouvaki |first3=Anthie |last4=Sgantzis |first4=Nikos |last5=Kotsoni |first5=Anastasia |last6=Alexiou |first6=Maria |last7=Harokopos |first7=Vaggelis |last8=Aidinis |first8=Vassilis |last9=Hemberger |first9=Myriam |last10=Kontoyiannis |first10=Dimitris L. |date=2009-05 |title=The RNA-binding protein Elavl1/HuR is essential for placental branching morphogenesis and embryonic development |url=https://pubmed.ncbi.nlm.nih.gov/19307312/ |journal=Molecular and Cellular Biology |volume=29 |issue=10 |pages=2762–2776 |doi=10.1128/MCB.01393-08 |issn=1098-5549 |pmc=2682039 |pmid=19307312}}</ref> Post-translational modifications of HuR, including [[phosphorylation]], [[Neddylation|NEDDylation]], [[methylation]], and [[ubiquitination]] each modulate the localization and expression of the protein in unique ways. Modifications such as methylation and ubiquitination alter the [[Affinity (biochemistry)|affinity]] of HuR to RNA.<ref name=":02">{{Cite journal |last=Doller |first=Anke |last2=Pfeilschifter |first2=Josef |last3=Eberhardt |first3=Wolfgang |date=2008 |title=Signalling pathways regulating nucleo-cytoplasmic shuttling of the mRNA-binding protein HuR |url=https://pubmed.ncbi.nlm.nih.gov/18585896/ |journal=Cellular Signalling |volume=20 |issue=12 |pages=2165–2173 |doi=10.1016/j.cellsig.2008.05.007 |issn=1873-3913 |pmid=18585896}}</ref> As an important regulator of post-transcriptional regulation, HuR destabilization from the mRNA is associated with degradation of the transcript.<ref>{{Cite journal |last=Brennan |first=C. M. |last2=Steitz* |first2=J. A. |date=2001-02-01 |title=HuR and mRNA stability |url=https://doi.org/10.1007/PL00000854 |journal=Cellular and Molecular Life Sciences CMLS |language=en |volume=58 |issue=2 |pages=266–277 |doi=10.1007/PL00000854 |issn=1420-9071}}</ref>
This RNA-binding protein has been found to be involved in a number of valuable cellular processes in mammals, including embryonic development, stress responses, and the immune system.<ref>{{Cite journal |last=Katsanou |first=Vicky |last2=Milatos |first2=Stavros |last3=Yiakouvaki |first3=Anthie |last4=Sgantzis |first4=Nikos |last5=Kotsoni |first5=Anastasia |last6=Alexiou |first6=Maria |last7=Harokopos |first7=Vaggelis |last8=Aidinis |first8=Vassilis |last9=Hemberger |first9=Myriam |last10=Kontoyiannis |first10=Dimitris L. |date=May 2009 |title=The RNA-binding protein Elavl1/HuR is essential for placental branching morphogenesis and embryonic development |url=https://pubmed.ncbi.nlm.nih.gov/19307312/ |journal=Molecular and Cellular Biology |volume=29 |issue=10 |pages=2762–2776 |doi=10.1128/MCB.01393-08 |issn=1098-5549 |pmc=2682039 |pmid=19307312}}</ref> Post-translational modifications of HuR, including [[phosphorylation]], [[Neddylation|NEDDylation]], [[methylation]], and [[ubiquitination]] each modulate the localization and expression of the protein in unique ways. Modifications such as methylation and ubiquitination alter the [[Affinity (biochemistry)|affinity]] of HuR to RNA.<ref name=":02">{{Cite journal |last=Doller |first=Anke |last2=Pfeilschifter |first2=Josef |last3=Eberhardt |first3=Wolfgang |date=2008 |title=Signalling pathways regulating nucleo-cytoplasmic shuttling of the mRNA-binding protein HuR |url=https://pubmed.ncbi.nlm.nih.gov/18585896/ |journal=Cellular Signalling |volume=20 |issue=12 |pages=2165–2173 |doi=10.1016/j.cellsig.2008.05.007 |issn=1873-3913 |pmid=18585896}}</ref> As an important regulator of post-transcriptional regulation, HuR destabilization from the mRNA is associated with degradation of the transcript.<ref>{{Cite journal |last=Brennan |first=C. M. |last2=Steitz* |first2=J. A. |date=2001-02-01 |title=HuR and mRNA stability |url=https://doi.org/10.1007/PL00000854 |journal=Cellular and Molecular Life Sciences |language=en |volume=58 |issue=2 |pages=266–277 |doi=10.1007/PL00000854 |issn=1420-9071}}</ref>


=== Phosphorylation ===
=== Phosphorylation ===
Phosphorylation of HuR can occur by [[Cyclin-dependent kinase|cyclin-dependent kinases]] (cdks), impacting its localization within the cell in a cell cycle-dependent fashion.<ref>{{Cite journal |last=Kim |first=Hyeon Ho |last2=Abdelmohsen |first2=Kotb |last3=Lal |first3=Ashish |last4=Pullmann |first4=Rudolf |last5=Yang |first5=Xiaoling |last6=Galban |first6=Stefanie |last7=Srikantan |first7=Subramanya |last8=Martindale |first8=Jennifer L. |last9=Blethrow |first9=Justin |last10=Shokat |first10=Kevan M. |last11=Gorospe |first11=Myriam |date=2008-07-01 |title=Nuclear HuR accumulation through phosphorylation by Cdk1 |url=http://genesdev.cshlp.org/content/22/13/1804 |journal=Genes & Development |language=en |volume=22 |issue=13 |pages=1804–1815 |doi=10.1101/gad.1645808 |issn=0890-9369 |pmid=18593881}}</ref> Additionally, checkpoint kinase 2 plays a significant role in phosphorylating HuR during [[Genotoxicity|genotoxic]] stress, promoting dissociation of HuR from its target mRNA transcript.<ref>{{Cite journal |last=Yu |first=Ting-Xi |last2=Wang |first2=Peng-Yuan |last3=Rao |first3=Jaladanki N. |last4=Zou |first4=Tongtong |last5=Liu |first5=Lan |last6=Xiao |first6=Lan |last7=Gorospe |first7=Myriam |last8=Wang |first8=Jian-Ying |date=2011 |title=Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function |url=https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkr567 |journal=Nucleic Acids Research |language=en |volume=39 |issue=19 |pages=8472–8487 |doi=10.1093/nar/gkr567 |issn=1362-4962 |pmc=PMC3201881 |pmid=21745814}}</ref>
Phosphorylation of HuR can occur by [[Cyclin-dependent kinase|cyclin-dependent kinases]] (cdks), impacting its localization within the cell in a cell cycle-dependent fashion.<ref>{{Cite journal |last=Kim |first=Hyeon Ho |last2=Abdelmohsen |first2=Kotb |last3=Lal |first3=Ashish |last4=Pullmann |first4=Rudolf |last5=Yang |first5=Xiaoling |last6=Galban |first6=Stefanie |last7=Srikantan |first7=Subramanya |last8=Martindale |first8=Jennifer L. |last9=Blethrow |first9=Justin |last10=Shokat |first10=Kevan M. |last11=Gorospe |first11=Myriam |date=2008-07-01 |title=Nuclear HuR accumulation through phosphorylation by Cdk1 |url=http://genesdev.cshlp.org/content/22/13/1804 |journal=Genes & Development |language=en |volume=22 |issue=13 |pages=1804–1815 |doi=10.1101/gad.1645808 |issn=0890-9369 |pmid=18593881}}</ref> Additionally, checkpoint kinase 2 plays a significant role in phosphorylating HuR during [[Genotoxicity|genotoxic]] stress, promoting dissociation of HuR from its target mRNA transcript.<ref>{{Cite journal |last=Yu |first=Ting-Xi |last2=Wang |first2=Peng-Yuan |last3=Rao |first3=Jaladanki N. |last4=Zou |first4=Tongtong |last5=Liu |first5=Lan |last6=Xiao |first6=Lan |last7=Gorospe |first7=Myriam |last8=Wang |first8=Jian-Ying |date=2011 |title=Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function |url=https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkr567 |journal=Nucleic Acids Research |language=en |volume=39 |issue=19 |pages=8472–8487 |doi=10.1093/nar/gkr567 |issn=1362-4962 |pmc=3201881 |pmid=21745814}}</ref>


=== Ubiquitination ===
=== Ubiquitination ===
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=== Methylation ===
=== Methylation ===
As is frequent in other mammalian proteins, HuR is methylated at arginine residues.<ref>{{Cite journal |last=Bedford |first=Mark T. |last2=Clarke |first2=Steven G. |date=2009 |title=Protein Arginine Methylation in Mammals: Who, What, and Why |url=https://doi.org/10.1016/j.molcel.2008.12.013 |journal=Molecular Cell |volume=33 |issue=1 |pages=1–13 |doi=10.1016/j.molcel.2008.12.013 |issn=1097-2765 |pmc=PMC3372459 |pmid=19150423}}</ref> For instance, protein arginine [[methyltransferase]] enzymes (PRMTs) methylate HuR to promote mRNA stabilization of certain target transcripts, such as ''[[Sirtuin 1|SIRT1]]'' in [[HeLa]] cells.<ref>{{Cite journal |last=Calvanese |first=Vincenzo |last2=Lara |first2=Ester |last3=Suárez-Álvarez |first3=Beatriz |last4=Abu Dawud |first4=Raed |last5=Vázquez-Chantada |first5=Mercedes |last6=Martínez-Chantar |first6=Maria Luz |last7=Embade |first7=Nieves |last8=López-Nieva |first8=Pilar |last9=Horrillo |first9=Angelica |last10=Hmadcha |first10=Abdelkrim |last11=Soria |first11=Bernat |last12=Piazzolla |first12=Daniela |last13=Herranz |first13=Daniel |last14=Serrano |first14=Manuel |last15=Mato |first15=Jose María |date=2010 |title=Sirtuin 1 regulation of developmental genes during differentiation of stem cells |url=https://pnas.org/doi/full/10.1073/pnas.1001399107 |journal=Proceedings of the National Academy of Sciences |language=en |volume=107 |issue=31 |pages=13736–13741 |doi=10.1073/pnas.1001399107 |issn=0027-8424 |pmc=PMC2922228 |pmid=20631301}}</ref>
As is frequent in other mammalian proteins, HuR is methylated at arginine residues.<ref>{{Cite journal |last=Bedford |first=Mark T. |last2=Clarke |first2=Steven G. |date=2009 |title=Protein Arginine Methylation in Mammals: Who, What, and Why |url=https://doi.org/10.1016/j.molcel.2008.12.013 |journal=Molecular Cell |volume=33 |issue=1 |pages=1–13 |doi=10.1016/j.molcel.2008.12.013 |issn=1097-2765 |pmc=3372459 |pmid=19150423}}</ref> For instance, protein arginine [[methyltransferase]] enzymes (PRMTs) methylate HuR to promote mRNA stabilization of certain target transcripts, such as ''[[Sirtuin 1|SIRT1]]'' in [[HeLa]] cells.<ref>{{Cite journal |last=Calvanese |first=Vincenzo |last2=Lara |first2=Ester |last3=Suárez-Álvarez |first3=Beatriz |last4=Abu Dawud |first4=Raed |last5=Vázquez-Chantada |first5=Mercedes |last6=Martínez-Chantar |first6=Maria Luz |last7=Embade |first7=Nieves |last8=López-Nieva |first8=Pilar |last9=Horrillo |first9=Angelica |last10=Hmadcha |first10=Abdelkrim |last11=Soria |first11=Bernat |last12=Piazzolla |first12=Daniela |last13=Herranz |first13=Daniel |last14=Serrano |first14=Manuel |last15=Mato |first15=Jose María |date=2010 |title=Sirtuin 1 regulation of developmental genes during differentiation of stem cells |url=https://pnas.org/doi/full/10.1073/pnas.1001399107 |journal=Proceedings of the National Academy of Sciences |language=en |volume=107 |issue=31 |pages=13736–13741 |doi=10.1073/pnas.1001399107 |issn=0027-8424 |pmc=2922228 |pmid=20631301}}</ref>


== Disease ==
== Disease ==
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{{Too much further reading|date=March 2017}}
{{Too much further reading|date=March 2017}}
{{refbegin | 2}}
{{refbegin | 2}}
*{{cite journal | vauthors=Nabors LB, Suswam E, Huang Y, Yang X, Johnson MJ, King PH |title=Tumor necrosis factor alpha induces angiogenic factor up-regulation in malignant glioma cells: a role for RNA stabilization and HuR |journal=Cancer Res. |volume=63 |issue= 14 |pages= 4181–7 |year= 2003 |pmid= 12874024 }}
*{{cite journal | vauthors=Nabors LB, Suswam E, Huang Y, Yang X, Johnson MJ, King PH |title=Tumor necrosis factor alpha induces angiogenic factor up-regulation in malignant glioma cells: a role for RNA stabilization and HuR |journal=Cancer Research |volume=63 |issue= 14 |pages= 4181–7 |year= 2003 |pmid= 12874024 }}
*{{cite journal | vauthors=Abdelmohsen K, Lal A, Kim HH, Gorospe M |title=Posttranscriptional orchestration of an anti-apoptotic program by HuR |journal=Cell Cycle |volume=6 |issue= 11 |pages= 1288–92 |year= 2007 |pmid= 17534146 |doi=10.4161/cc.6.11.4299 |doi-access=free }}
*{{cite journal | vauthors=Abdelmohsen K, Lal A, Kim HH, Gorospe M |title=Posttranscriptional orchestration of an anti-apoptotic program by HuR |journal=Cell Cycle |volume=6 |issue= 11 |pages= 1288–92 |year= 2007 |pmid= 17534146 |doi=10.4161/cc.6.11.4299 |doi-access=free }}
*{{cite journal | vauthors=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery |journal=Genome Res. |volume=6 |issue= 9 |pages= 791–806 |year= 1997 |pmid= 8889548 |doi=10.1101/gr.6.9.791 |doi-access=free }}
*{{cite journal | vauthors=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery |journal=Genome Res. |volume=6 |issue= 9 |pages= 791–806 |year= 1997 |pmid= 8889548 |doi=10.1101/gr.6.9.791 |doi-access=free }}
*{{cite journal | vauthors=Sakai K, Kitagawa Y, Hirose G |title=Analysis of the RNA recognition motifs of human neuronal ELAV-like proteins in binding to a cytokine mRNA |journal=Biochem. Biophys. Res. Commun. |volume=256 |issue= 2 |pages= 263–268 |year= 1999 |pmid= 10079173 |doi= 10.1006/bbrc.1999.0282 }}
*{{cite journal | vauthors=Sakai K, Kitagawa Y, Hirose G |title=Analysis of the RNA recognition motifs of human neuronal ELAV-like proteins in binding to a cytokine mRNA |journal=Biochem. Biophys. Res. Commun. |volume=256 |issue= 2 |pages= 263–268 |year= 1999 |pmid= 10079173 |doi= 10.1006/bbrc.1999.0282 }}
*{{cite journal | author=Wang W |title=HuR regulates p21 mRNA stabilization by UV light |journal=Mol. Cell. Biol. |volume=20 |issue= 3 |pages= 760–769 |year= 2000 |pmid= 10629032 |doi=10.1128/MCB.20.3.760-769.2000 | pmc=85192 |name-list-style=vanc| author2=Furneaux H | author3=Cheng H | last4=Caldwell | first4=M. C. | last5=Hutter | first5=D. | last6=Liu | first6=Y. | last7=Holbrook | first7=N. | last8=Gorospe | first8=M. }}
*{{cite journal | author=Wang W |title=HuR regulates p21 mRNA stabilization by UV light |journal=Molecular and Cellular Biology |volume=20 |issue= 3 |pages= 760–769 |year= 2000 |pmid= 10629032 |doi=10.1128/MCB.20.3.760-769.2000 | pmc=85192 |name-list-style=vanc| author2=Furneaux H | author3=Cheng H | last4=Caldwell | first4=M. C. | last5=Hutter | first5=D. | last6=Liu | first6=Y. | last7=Holbrook | first7=N. | last8=Gorospe | first8=M. }}
*{{cite journal | author=Blaxall BC |title=Purification and characterization of beta-adrenergic receptor mRNA-binding proteins |journal=J. Biol. Chem. |volume=275 |issue= 6 |pages= 4290–4297 |year= 2000 |pmid= 10660597 |doi=10.1074/jbc.275.6.4290 |name-list-style=vanc| author2=Pellett AC | author3=Wu SC | last4=Pende | first4=A | last5=Port | first5=JD |doi-access=free}}
*{{cite journal | author=Blaxall BC |title=Purification and characterization of beta-adrenergic receptor mRNA-binding proteins |journal=Journal of Biological Chemistry |volume=275 |issue= 6 |pages= 4290–4297 |year= 2000 |pmid= 10660597 |doi=10.1074/jbc.275.6.4290 |name-list-style=vanc| author2=Pellett AC | author3=Wu SC | last4=Pende | first4=A | last5=Port | first5=JD |doi-access=free}}
*{{cite journal | author=Park S |title=HuD RNA recognition motifs play distinct roles in the formation of a stable complex with AU-rich RNA |journal=Mol. Cell. Biol. |volume=20 |issue= 13 |pages= 4765–4772 |year= 2000 |pmid= 10848602 |doi=10.1128/MCB.20.13.4765-4772.2000 | pmc=85909 |name-list-style=vanc| author2=Myszka DG | author3=Yu M | last4=Littler | first4=S. J. | last5=Laird-Offringa | first5=I. A. }}
*{{cite journal | author=Park S |title=HuD RNA recognition motifs play distinct roles in the formation of a stable complex with AU-rich RNA |journal=Molecular and Cellular Biology |volume=20 |issue= 13 |pages= 4765–4772 |year= 2000 |pmid= 10848602 |doi=10.1128/MCB.20.13.4765-4772.2000 | pmc=85909 |name-list-style=vanc| author2=Myszka DG | author3=Yu M | last4=Littler | first4=S. J. | last5=Laird-Offringa | first5=I. A. }}
*{{cite journal | vauthors=Spångberg K, Wiklund L, Schwartz S |title=HuR, a protein implicated in oncogene and growth factor mRNA decay, binds to the 3' ends of hepatitis C virus RNA of both polarities |journal=Virology |volume=274 |issue= 2 |pages= 378–390 |year= 2000 |pmid= 10964780 |doi= 10.1006/viro.2000.0461 |doi-access= free }}
*{{cite journal | vauthors=Spångberg K, Wiklund L, Schwartz S |title=HuR, a protein implicated in oncogene and growth factor mRNA decay, binds to the 3' ends of hepatitis C virus RNA of both polarities |journal=Virology |volume=274 |issue= 2 |pages= 378–390 |year= 2000 |pmid= 10964780 |doi= 10.1006/viro.2000.0461 |doi-access= free }}
*{{cite journal | vauthors=Brennan CM, Gallouzi IE, Steitz JA |title=Protein ligands to HuR modulate its interaction with target mRNAs in vivo |journal=J. Cell Biol. |volume=151 |issue= 1 |pages= 1–14 |year= 2000 |pmid= 11018049 |doi=10.1083/jcb.151.1.1 | pmc=2189805 }}
*{{cite journal | vauthors=Brennan CM, Gallouzi IE, Steitz JA |title=Protein ligands to HuR modulate its interaction with target mRNAs in vivo |journal=J. Cell Biol. |volume=151 |issue= 1 |pages= 1–14 |year= 2000 |pmid= 11018049 |doi=10.1083/jcb.151.1.1 | pmc=2189805 }}
*{{cite journal | vauthors=Gallouzi IE, Steitz JA |title=Delineation of mRNA export pathways by the use of cell-permeable peptides |journal=Science |volume=294 |issue= 5548 |pages= 1895–1901 |year= 2001 |pmid= 11729309 |doi= 10.1126/science.1064693 |bibcode=2001Sci...294.1895G |s2cid=43726887 }}
*{{cite journal | vauthors=Gallouzi IE, Steitz JA |title=Delineation of mRNA export pathways by the use of cell-permeable peptides |journal=Science |volume=294 |issue= 5548 |pages= 1895–1901 |year= 2001 |pmid= 11729309 |doi= 10.1126/science.1064693 |bibcode=2001Sci...294.1895G |s2cid=43726887 }}
*{{cite journal | vauthors=Goldberg-Cohen I, Furneauxb H, Levy AP |title=A 40-bp RNA element that mediates stabilization of vascular endothelial growth factor mRNA by HuR |journal=J. Biol. Chem. |volume=277 |issue= 16 |pages= 13635–13640 |year= 2002 |pmid= 11834731 |doi= 10.1074/jbc.M108703200 |doi-access= free }}
*{{cite journal | vauthors=Goldberg-Cohen I, Furneauxb H, Levy AP |title=A 40-bp RNA element that mediates stabilization of vascular endothelial growth factor mRNA by HuR |journal=Journal of Biological Chemistry |volume=277 |issue= 16 |pages= 13635–13640 |year= 2002 |pmid= 11834731 |doi= 10.1074/jbc.M108703200 |doi-access= free }}
*{{cite journal | author=Wang W |title=AMP-activated kinase regulates cytoplasmic HuR |journal=Mol. Cell. Biol. |volume=22 |issue= 10 |pages= 3425–3436 |year= 2002 |pmid= 11971974 |doi=10.1128/MCB.22.10.3425-3436.2002 | pmc=133799 |name-list-style=vanc| author2=Fan J | author3=Yang X | last4=Furer-Galban | first4=S. | last5=Lopez De Silanes | first5=I. | last6=Von Kobbe | first6=C. | last7=Guo | first7=J. | last8=Georas | first8=S. N. | last9=Foufelle | first9=F. }}
*{{cite journal | author=Wang W |title=AMP-activated kinase regulates cytoplasmic HuR |journal=Molecular and Cellular Biology |volume=22 |issue= 10 |pages= 3425–3436 |year= 2002 |pmid= 11971974 |doi=10.1128/MCB.22.10.3425-3436.2002 | pmc=133799 |name-list-style=vanc| author2=Fan J | author3=Yang X | last4=Furer-Galban | first4=S. | last5=Lopez De Silanes | first5=I. | last6=Von Kobbe | first6=C. | last7=Guo | first7=J. | last8=Georas | first8=S. N. | last9=Foufelle | first9=F. }}
*{{cite journal | author=Yeap BB |title=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 |journal=J. Biol. Chem. |volume=277 |issue= 30 |pages= 27183–27192 |year= 2002 |pmid= 12011088 |doi= 10.1074/jbc.M202883200 |name-list-style=vanc| author2=Voon DC | author3=Vivian JP | last4=McCulloch | first4=RK | last5=Thomson | first5=AM | last6=Giles | first6=KM | last7=Czyzyk-Krzeska | first7=MF | last8=Furneaux | first8=H | last9=Wilce | first9=MC | doi-access=free }}
*{{cite journal | author=Yeap BB |title=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 |journal=Journal of Biological Chemistry |volume=277 |issue= 30 |pages= 27183–27192 |year= 2002 |pmid= 12011088 |doi= 10.1074/jbc.M202883200 |name-list-style=vanc| author2=Voon DC | author3=Vivian JP | last4=McCulloch | first4=RK | last5=Thomson | first5=AM | last6=Giles | first6=KM | last7=Czyzyk-Krzeska | first7=MF | last8=Furneaux | first8=H | last9=Wilce | first9=MC | doi-access=free }}
*{{cite journal | author=Li H |title=Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1. Coactivator-associated arginine methyltransferase |journal=J. Biol. Chem. |volume=277 |issue= 47 |pages= 44623–44630 |year= 2003 |pmid= 12237300 |doi= 10.1074/jbc.M206187200 |name-list-style=vanc| author2=Park S | author3=Kilburn B | last4=Jelinek | first4=MA | last5=Henschen-Edman | first5=A | last6=Aswad | first6=DW | last7=Stallcup | first7=MR | last8=Laird-Offringa | first8=IA | doi-access=free }}
*{{cite journal | author=Li H |title=Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1. Coactivator-associated arginine methyltransferase |journal=Journal of Biological Chemistry |volume=277 |issue= 47 |pages= 44623–44630 |year= 2003 |pmid= 12237300 |doi= 10.1074/jbc.M206187200 |name-list-style=vanc| author2=Park S | author3=Kilburn B | last4=Jelinek | first4=MA | last5=Henschen-Edman | first5=A | last6=Aswad | first6=DW | last7=Stallcup | first7=MR | last8=Laird-Offringa | first8=IA | doi-access=free }}
*{{cite journal | vauthors=Chen CY, Xu N, Shyu AB |title=Highly selective actions of HuR in antagonizing AU-rich element-mediated mRNA destabilization |journal=Mol. Cell. Biol. |volume=22 |issue= 20 |pages= 7268–7278 |year= 2002 |pmid= 12242302 |doi=10.1128/MCB.22.20.7268-7278.2002 | pmc=139819 }}
*{{cite journal | vauthors=Chen CY, Xu N, Shyu AB |title=Highly selective actions of HuR in antagonizing AU-rich element-mediated mRNA destabilization |journal=Molecular and Cellular Biology |volume=22 |issue= 20 |pages= 7268–7278 |year= 2002 |pmid= 12242302 |doi=10.1128/MCB.22.20.7268-7278.2002 | pmc=139819 }}
*{{cite journal | author=Giles KM |title=The 3'-untranslated region of p21WAF1 mRNA is a composite cis-acting sequence bound by RNA-binding proteins from breast cancer cells, including HuR and poly(C)-binding protein |journal=J. Biol. Chem. |volume=278 |issue= 5 |pages= 2937–2946 |year= 2003 |pmid= 12431987 |doi= 10.1074/jbc.M208439200 |name-list-style=vanc| author2=Daly JM | author3=Beveridge DJ | last4=Thomson | first4=A. M. | last5=Voon | first5=D. C. | last6=Furneaux | first6=H. M. | last7=Jazayeri | first7=J. A. | last8=Leedman | first8=P. J. | doi-access=free }}
*{{cite journal | author=Giles KM |title=The 3'-untranslated region of p21WAF1 mRNA is a composite cis-acting sequence bound by RNA-binding proteins from breast cancer cells, including HuR and poly(C)-binding protein |journal=Journal of Biological Chemistry |volume=278 |issue= 5 |pages= 2937–2946 |year= 2003 |pmid= 12431987 |doi= 10.1074/jbc.M208439200 |name-list-style=vanc| author2=Daly JM | author3=Beveridge DJ | last4=Thomson | first4=A. M. | last5=Voon | first5=D. C. | last6=Furneaux | first6=H. M. | last7=Jazayeri | first7=J. A. | last8=Leedman | first8=P. J. | doi-access=free }}
*{{cite journal | author=Strausberg RL |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–16903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 |name-list-style=vanc| author2=Feingold EA | author3=Grouse LH | last4=Derge | first4=JG | last5=Klausner | first5=RD | last6=Collins | first6=FS | last7=Wagner | first7=L | last8=Shenmen | first8=CM | last9=Schuler | first9=GD | bibcode=2002PNAS...9916899M |doi-access=free }}
*{{cite journal | author=Strausberg RL |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–16903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 |name-list-style=vanc| author2=Feingold EA | author3=Grouse LH | last4=Derge | first4=JG | last5=Klausner | first5=RD | last6=Collins | first6=FS | last7=Wagner | first7=L | last8=Shenmen | first8=CM | last9=Schuler | first9=GD | bibcode=2002PNAS...9916899M |doi-access=free }}
*{{cite journal | author=Wang W |title=Increased AMP:ATP ratio and AMP-activated protein kinase activity during cellular senescence linked to reduced HuR function |journal=J. Biol. Chem. |volume=278 |issue= 29 |pages= 27016–27023 |year= 2003 |pmid= 12730239 |doi= 10.1074/jbc.M300318200 |name-list-style=vanc| author2=Yang X | author3=López de Silanes I | last4=Carling | first4=D | last5=Gorospe | first5=M |doi-access=free }}
*{{cite journal | author=Wang W |title=Increased AMP:ATP ratio and AMP-activated protein kinase activity during cellular senescence linked to reduced HuR function |journal=Journal of Biological Chemistry |volume=278 |issue= 29 |pages= 27016–27023 |year= 2003 |pmid= 12730239 |doi= 10.1074/jbc.M300318200 |name-list-style=vanc| author2=Yang X | author3=López de Silanes I | last4=Carling | first4=D | last5=Gorospe | first5=M |doi-access=free }}
{{refend}}
{{refend}}


== External links ==
== External links ==
* [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/Q15717 PDBe-KB] provides an overview of all the structure information available in the PDB for Human ELAV-like protein 1
* [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/Q15717 PDBe-KB] provides an overview of all the structure information available in the PDB for Human ELAV-like protein 1





{{NLM content|url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=1994}}
{{NLM content|url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=1994}}





Revision as of 00:33, 29 April 2024

ELAVL1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesELAVL1, ELAV1, HUR, Hua, MelG, ELAV like RNA binding protein 1, HuR
External IDsOMIM: 603466 MGI: 1100851 HomoloGene: 20367 GeneCards: ELAVL1
Orthologs
SpeciesHumanMouse
Entrez

1994

15568

Ensembl

ENSG00000066044

ENSMUSG00000040028

UniProt

Q15717

P70372

RefSeq (mRNA)

NM_001419

NM_010485

RefSeq (protein)

NP_001410

NP_034615

Location (UCSC)Chr 19: 7.96 – 8.01 MbChr 8: 4.34 – 4.38 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

ELAV-like protein 1 or HuR (human antigen R) is a protein that in humans is encoded by the ELAVL1 gene.[5][6]

The protein encoded by this gene is a member of the ELAVL protein family. This encoded protein contains 3 RNA-binding domains and binds cis-acting AU-rich elements in 3' untranslated regions. One of its best-known functions is to stabilize mRNAs in order to regulate gene expression.[7] Various post-translational modifications of HuR influence its subcellular localization and stability of binding to mRNAs.[8]

Structure

Of the RNA-binding ELAV/Hu family of proteins in mammals, HuR is the only ubiquitously expressed one, whereas the other three are primarily found in neuronal tissue.[9] Having a well-conserved primary structure to its family members, HuR has two adjacent RNA recognition motifs (RRMs) proximal to the N-terminus, followed by a flexible hinge region next to a final RRM at the C-terminus.[5] The RRM domains of HuR each contain two alpha helices with several antiparallel beta sheets in their secondary structure, a 20 amino-acid long N-terminus before RRM1 and RRM2, and a 12 amino acid linker connecting them.[10][11] The hinge region connecting RRM1,2 to RRM3 is 60 amino acids long.[11]

RNA Binding

The RRM1 domain appears to be the principal RNA-binding portion with RRM2 contributing some more contacts.[11] According to crystal structure studies, RRM1,2 domains correspond to a "moderately specific" predicted consensus sequence.[12][13] Additionally, RRM3 contributes to dimerization and oligomerization of HuR, supporting binding to AU-rich elements of RNA by the other domains, but RRM3 itself has moderate binding strength to RNA.[12] RRM3 has been shown to bind to long poly-A tails and AU-rich RNAs.[14][15]

Function

This RNA-binding protein has been found to be involved in a number of valuable cellular processes in mammals, including embryonic development, stress responses, and the immune system.[16] Post-translational modifications of HuR, including phosphorylation, NEDDylation, methylation, and ubiquitination each modulate the localization and expression of the protein in unique ways. Modifications such as methylation and ubiquitination alter the affinity of HuR to RNA.[17] As an important regulator of post-transcriptional regulation, HuR destabilization from the mRNA is associated with degradation of the transcript.[18]

Phosphorylation

Phosphorylation of HuR can occur by cyclin-dependent kinases (cdks), impacting its localization within the cell in a cell cycle-dependent fashion.[19] Additionally, checkpoint kinase 2 plays a significant role in phosphorylating HuR during genotoxic stress, promoting dissociation of HuR from its target mRNA transcript.[20]

Ubiquitination

The ubiquitination of HuR by an E3 ligase in many cases results in proteasomal degradation. For instance, the esophageal tumor suppressor ECRG2, ubiquitinates HuR during DNA damage, promoting its degradation.[21] However, in other cases, ubiquitination promotes dissociation of HuR from its transcript, such as ubiquitination of certain lysine residues of the RRM3 domain leading to detachment from the mRNA transcript of P21 and other tumor suppressors.[22]

Methylation

As is frequent in other mammalian proteins, HuR is methylated at arginine residues.[23] For instance, protein arginine methyltransferase enzymes (PRMTs) methylate HuR to promote mRNA stabilization of certain target transcripts, such as SIRT1 in HeLa cells.[24]

Disease

Cancer

Although HuR has a vital role in transcriptosomal regulation, there is an apparent up-regulation of HuR in several types of cancer that correlates with a malignant or metastatic status that has increased the relevance of HuR as a potential therapeutic target for a number of cancer studies. The abundance of HuR suggests a tumorigenic promotion of angiogenesis, cellular proliferation, and anti-apoptotic properties in cancer cells, purportedly due to the impact of mRNA stabilization and its ubiquitous presence in human tissue.[25]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000066044 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040028 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b Ma WJ, Cheng S, Campbell C, et al. (Jun 1996). "Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein". Journal of Biological Chemistry. 271 (14): 8144–8151. doi:10.1074/jbc.271.14.8144. PMID 8626503.
  6. ^ Ma WJ, Furneaux H (Feb 1997). "Localization of the human HuR gene to chromosome 19p13.2". Human Genetics. 99 (1): 32–33. doi:10.1007/s004390050305. PMID 9003489. S2CID 32509747.
  7. ^ "Entrez Gene: ELAVL1 ELAV (embryonic lethal, abnormal vision, Drosophila)-like 1 (Hu antigen R)".
  8. ^ Doller, Anke; Pfeilschifter, Josef; Eberhardt, Wolfgang (2008). "Signalling pathways regulating nucleo-cytoplasmic shuttling of the mRNA-binding protein HuR". Cellular Signalling. 20 (12): 2165–2173. doi:10.1016/j.cellsig.2008.05.007. ISSN 1873-3913. PMID 18585896.
  9. ^ Antic, Dragana; Keene, Jack D. (1997-08-01). "Embryonic Lethal Abnormal Visual RNA-Binding Proteins Involved in Growth, Differentiation, and Posttranscriptional Gene Expression". The American Journal of Human Genetics. 61 (2): 273–278. doi:10.1086/514866. ISSN 0002-9297.
  10. ^ Cléry, Antoine; Blatter, Markus; Allain, Frédéric H.-T. (2008). "RNA recognition motifs: boring? Not quite". Current Opinion in Structural Biology. 18 (3): 290–298. doi:10.1016/j.sbi.2008.04.002. ISSN 0959-440X. PMID 18515081.
  11. ^ a b c Wang, Hong; Zeng, Fuxing; Liu, Qiao; et al. (2013). "The structure of the ARE-binding domains of Hu antigen R (HuR) undergoes conformational changes during RNA binding". Acta Crystallographica. Section D, Biological Crystallography. 69 (Pt 3): 373–380. doi:10.1107/S0907444912047828. ISSN 1399-0047. PMID 23519412.
  12. ^ a b Pabis, Marta; Popowicz, Grzegorz M.; Stehle, Ralf; et al. (2019-01-25). "HuR biological function involves RRM3-mediated dimerization and RNA binding by all three RRMs". Nucleic Acids Research. 47 (2): 1011–1029. doi:10.1093/nar/gky1138. ISSN 1362-4962. PMC 6344896. PMID 30418581.
  13. ^ Wang, X.; Tanaka Hall, T. M. (2001). "Structural basis for recognition of AU-rich element RNA by the HuD protein". Nature Structural Biology. 8 (2): 141–145. doi:10.1038/84131. ISSN 1072-8368. PMID 11175903.
  14. ^ Ma, W J; Chung, S; Furneaux, H (1997-09-15). "The Elav-like proteins bind to AU-rich elements and to the poly(A) tail of mRNA". Nucleic Acids Research. 25 (18): 3564–3569. ISSN 0305-1048. PMID 9278474.
  15. ^ Ma, W J; Chung, S; Furneaux, H (1997-09-15). "The Elav-like proteins bind to AU-rich elements and to the poly(A) tail of mRNA". Nucleic Acids Research. 25 (18): 3564–3569. ISSN 0305-1048. PMID 9278474.
  16. ^ Katsanou, Vicky; Milatos, Stavros; Yiakouvaki, Anthie; et al. (May 2009). "The RNA-binding protein Elavl1/HuR is essential for placental branching morphogenesis and embryonic development". Molecular and Cellular Biology. 29 (10): 2762–2776. doi:10.1128/MCB.01393-08. ISSN 1098-5549. PMC 2682039. PMID 19307312.
  17. ^ Doller, Anke; Pfeilschifter, Josef; Eberhardt, Wolfgang (2008). "Signalling pathways regulating nucleo-cytoplasmic shuttling of the mRNA-binding protein HuR". Cellular Signalling. 20 (12): 2165–2173. doi:10.1016/j.cellsig.2008.05.007. ISSN 1873-3913. PMID 18585896.
  18. ^ Brennan, C. M.; Steitz*, J. A. (2001-02-01). "HuR and mRNA stability". Cellular and Molecular Life Sciences. 58 (2): 266–277. doi:10.1007/PL00000854. ISSN 1420-9071.
  19. ^ Kim, Hyeon Ho; Abdelmohsen, Kotb; Lal, Ashish; et al. (2008-07-01). "Nuclear HuR accumulation through phosphorylation by Cdk1". Genes & Development. 22 (13): 1804–1815. doi:10.1101/gad.1645808. ISSN 0890-9369. PMID 18593881.
  20. ^ Yu, Ting-Xi; Wang, Peng-Yuan; Rao, Jaladanki N.; et al. (2011). "Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function". Nucleic Acids Research. 39 (19): 8472–8487. doi:10.1093/nar/gkr567. ISSN 1362-4962. PMC 3201881. PMID 21745814.
  21. ^ Lucchesi, C.; Sheikh, M. S.; Huang, Y. (2016). "Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2". Oncogene. 35 (20): 2565–2573. doi:10.1038/onc.2015.339. ISSN 1476-5594.
  22. ^ Zhou, Hua-Lin; Geng, Cuiyu; Luo, Guangbin; et al. (2013-05-01). "The p97–UBXD8 complex destabilizes mRNA by promoting release of ubiquitinated HuR from mRNP". Genes & Development. 27 (9): 1046–1058. doi:10.1101/gad.215681.113. ISSN 0890-9369. PMID 23618873.
  23. ^ Bedford, Mark T.; Clarke, Steven G. (2009). "Protein Arginine Methylation in Mammals: Who, What, and Why". Molecular Cell. 33 (1): 1–13. doi:10.1016/j.molcel.2008.12.013. ISSN 1097-2765. PMC 3372459. PMID 19150423.
  24. ^ Calvanese, Vincenzo; Lara, Ester; Suárez-Álvarez, Beatriz; et al. (2010). "Sirtuin 1 regulation of developmental genes during differentiation of stem cells". Proceedings of the National Academy of Sciences. 107 (31): 13736–13741. doi:10.1073/pnas.1001399107. ISSN 0027-8424. PMC 2922228. PMID 20631301.
  25. ^ Abdelmohsen, Kotb; Gorospe, Myriam (2010). "Posttranscriptional regulation of cancer traits by HuR". Wiley interdisciplinary reviews. RNA. 1 (2): 214–229. doi:10.1002/wrna.4. ISSN 1757-7012. PMC 3808850. PMID 21935886.

Further reading

External links

  • PDBe-KB provides an overview of all the structure information available in the PDB for Human ELAV-like protein 1


This article incorporates text from the United States National Library of Medicine ([1]), which is in the public domain.


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