This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chen, C.-Y. A.
Right arrow Articles by Shyu, A.-B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chen, C.-Y. A.
Right arrow Articles by Shyu, A.-B.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, October 2002, p. 7268-7278, Vol. 22, No. 20
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.20.7268-7278.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Highly Selective Actions of HuR in Antagonizing AU-Rich Element-Mediated mRNA Destabilization

Chyi-Ying A. Chen, Nianhua Xu, and Ann-Bin Shyu*

Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, Texas 77030

Received 23 May 2002/ Returned for modification 1 July 2002/ Accepted 9 July 2002

Human RNA-binding protein HuR, a nucleocytoplasmic shuttling protein, is a ubiquitously expressed member of the family of Hu proteins, which consist of two N-terminal RNA recognition motifs (RRM1 and RRM2), a hinge region, and a C-terminal RRM (RRM3). Although in vitro experiments showed indiscriminate binding of Hu proteins synthesized in bacterial systems to many different AU-rich elements (AREs), in vivo studies have pointed to a cytoplasmic role for HuR protein in antagonizing the rapid decay of some specific ARE-containing mRNAs, depending on physiological situations. By ectopically overexpressing HuR and its mutant derivatives in NIH 3T3 cells to mimic HuR upregulation of specific ARE-containing mRNAs in other systems, we have examined the in vivo ARE-binding specificity of HuR and dissected its functionally critical domains. We show that in NIH 3T3 cells, HuR stabilizes reporter messages containing only the c-fos ARE and not other AREs. Two distinct binding sites were identified within the c-fos ARE, the 5' AUUUA-containing domain and the 3' U-stretch-containing domain. These actions of HuR are markedly different from those of another ARE-binding protein, hnRNP D (also termed AUF1), which in vivo recognizes AUUUA repeats found in cytokine AREs and can exert both stabilizing and destabilizing effects. Further experiments showed that any combination of two of the three RRM domains of HuR is sufficient for strong binding to the c-fos ARE in vitro and to exert an RNA stabilization effect in vivo comparable to that of intact HuR and that the hinge region containing nucleocytoplasmic shuttling signals is dispensable for the stabilization effect of HuR. Our data suggest that the ARE-binding specificity of HuR in vivo is modulated to interact only with and thus regulate specific AREs in a cell type- and physiological state-dependent manner.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, TX 77030. Phone: (713) 500-6068. Fax: (713) 500-0652. E-mail: Ann-Bin.Shyu{at}uth.tmc.edu.

Molecular and Cellular Biology, October 2002, p. 7268-7278, Vol. 22, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.20.7268-7278.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Al-Ahmadi, W., Al-Ghamdi, M., Al-Haj, L., Al-Saif, M., Khabar, K. S. A. (2009). Alternative polyadenylation variants of the RNA binding protein, HuR: abundance, role of AU-rich elements and auto-Regulation. Nucleic Acids Res 37: 3612-3624 [Abstract] [Full Text]  
  • Duan, H., Cherradi, N., Feige, J.-J., Jefcoate, C. (2009). cAMP-Dependent Posttranscriptional Regulation of Steroidogenic Acute Regulatory (STAR) Protein by the Zinc Finger Protein ZFP36L1/TIS11b. Mol. Endocrinol. 23: 497-509 [Abstract] [Full Text]  
  • Abdelmohsen, K., Srikantan, S., Kuwano, Y., Gorospe, M. (2008). miR-519 reduces cell proliferation by lowering RNA-binding protein HuR levels. Proc. Natl. Acad. Sci. USA 105: 20297-20302 [Abstract] [Full Text]  
  • Mazan-Mamczarz, K., Hagner, P. R., Dai, B., Wood, W. H., Zhang, Y., Becker, K. G., Liu, Z., Gartenhaus, R. B. (2008). Identification of Transformation-Related Pathways in a Breast Epithelial Cell Model Using a Ribonomics Approach. Cancer Res. 68: 7730-7735 [Abstract] [Full Text]  
  • Nechama, M., Ben-Dov, I. Z., Briata, P., Gherzi, R., Naveh-Many, T. (2008). The mRNA decay promoting factor K-homology splicing regulator protein post-transcriptionally determines parathyroid hormone mRNA levels. FASEB J. 22: 3458-3468 [Abstract] [Full Text]  
  • Estevez, A. M. (2008). The RNA-binding protein TbDRBD3 regulates the stability of a specific subset of mRNAs in trypanosomes. Nucleic Acids Res 36: 4573-4586 [Abstract] [Full Text]  
  • Kuwano, Y., Kim, H. H., Abdelmohsen, K., Pullmann, R. Jr., Martindale, J. L., Yang, X., Gorospe, M. (2008). MKP-1 mRNA Stabilization and Translational Control by RNA-Binding Proteins HuR and NF90. Mol. Cell. Biol. 28: 4562-4575 [Abstract] [Full Text]  
  • Izquierdo, J. M. (2008). Hu Antigen R (HuR) Functions as an Alternative Pre-mRNA Splicing Regulator of Fas Apoptosis-promoting Receptor on Exon Definition. J. Biol. Chem. 283: 19077-19084 [Abstract] [Full Text]  
  • Kandasamy, K., Kraft, A. S. (2008). Proteasome inhibitor PS-341 (VELCADE) induces stabilization of the TRAIL receptor DR5 mRNA through the 3'-untranslated region. Molecular Cancer Therapeutics 7: 1091-1100 [Abstract] [Full Text]  
  • Natarajan, G., Ramalingam, S., Ramachandran, I., May, R., Queimado, L., Houchen, C. W., Anant, S. (2008). CUGBP2 downregulation by prostaglandin E2 protects colon cancer cells from radiation-induced mitotic catastrophe. Am. J. Physiol. Gastrointest. Liver Physiol. 294: G1235-G1244 [Abstract] [Full Text]  
  • Suswam, E., Li, Y., Zhang, X., Gillespie, G. Y., Li, X., Shacka, J. J., Lu, L., Zheng, L., King, P. H. (2008). Tristetraprolin Down-regulates Interleukin-8 and Vascular Endothelial Growth Factor in Malignant Glioma Cells. Cancer Res. 68: 674-682 [Abstract] [Full Text]  
  • Panebra, A., Schwarb, M. R., Swift, S. M., Weiss, S. T., Bleecker, E. R., Hawkins, G. A., Liggett, S. B. (2008). Variable-length poly-C tract polymorphisms of the {beta}2-adrenergic receptor 3'-UTR alter expression and agonist regulation. Am. J. Physiol. Lung Cell. Mol. Physiol. 294: L190-L195 [Abstract] [Full Text]  
  • Quann, E. J., Khwaja, F., Djakiew, D. (2007). The p38 MAPK Pathway Mediates Aryl Propionic Acid Induced Messenger RNA Stability of p75NTR in Prostate Cancer Cells. Cancer Res. 67: 11402-11410 [Abstract] [Full Text]  
  • Lu, L., Zheng, L., Viera, L., Suswam, E., Li, Y., Li, X., Estevez, A. G., King, P. H. (2007). Mutant Cu/Zn-Superoxide Dismutase Associated with Amyotrophic Lateral Sclerosis Destabilizes Vascular Endothelial Growth Factor mRNA and Downregulates Its Expression. J. Neurosci. 27: 7929-7938 [Abstract] [Full Text]  
  • Fialcowitz-White, E. J., Brewer, B. Y., Ballin, J. D., Willis, C. D., Toth, E. A., Wilson, G. M. (2007). Specific Protein Domains Mediate Cooperative Assembly of HuR Oligomers on AU-rich mRNA-destabilizing Sequences. J. Biol. Chem. 282: 20948-20959 [Abstract] [Full Text]  
  • Chateauvieux, S., Ichante, J.-L., Delorme, B., Frouin, V., Pietu, G., Langonne, A., Gallay, N., Sensebe, L., Martin, M. T., Moore, K. A., Charbord, P. (2007). Molecular profile of mouse stromal mesenchymal stem cells. Physiol. Genomics 29: 128-138 [Abstract] [Full Text]  
  • Guo, X., Ma, J., Sun, J., Gao, G. (2007). The zinc-finger antiviral protein recruits the RNA processing exosome to degrade the target mRNA. Proc. Natl. Acad. Sci. USA 104: 151-156 [Abstract] [Full Text]  
  • Hawkins, G. A., Tantisira, K., Meyers, D. A., Ampleford, E. J., Moore, W. C., Klanderman, B., Liggett, S. B., Peters, S. P., Weiss, S. T., Bleecker, E. R. (2006). Sequence, Haplotype, and Association Analysis of ADRbeta2 in a Multiethnic Asthma Case-Control Study. Am. J. Respir. Crit. Care Med. 174: 1101-1109 [Abstract] [Full Text]  
  • Yarovinsky, T. O., Butler, N. S., Monick, M. M., Hunninghake, G. W. (2006). Early Exposure to IL-4 Stabilizes IL-4 mRNA in CD4+ T Cells via RNA-Binding Protein HuR. J. Immunol. 177: 4426-4435 [Abstract] [Full Text]  
  • Prechtel, A. T., Chemnitz, J., Schirmer, S., Ehlers, C., Langbein-Detsch, I., Stulke, J., Dabauvalle, M.-C., Kehlenbach, R. H., Hauber, J. (2006). Expression of CD83 Is Regulated by HuR via a Novel cis-Active Coding Region RNA Element. J. Biol. Chem. 281: 10912-10925 [Abstract] [Full Text]  
  • Cherradi, N., Lejczak, C., Desroches-Castan, A., Feige, J.-J. (2006). Antagonistic Functions of Tetradecanoyl Phorbol Acetate-Inducible-Sequence 11b and HuR in the Hormonal Regulation of Vascular Endothelial Growth Factor Messenger Ribonucleic Acid Stability by Adrenocorticotropin. Mol. Endocrinol. 20: 916-930 [Abstract] [Full Text]  
  • Barreau, C., Paillard, L., Osborne, H. B. (2006). AU-rich elements and associated factors: are there unifying principles?. Nucleic Acids Res 33: 7138-7150 [Abstract] [Full Text]  
  • Blum, J. L., Samarel, A. M., Mestril, R. (2005). Phosphorylation and binding of AUF1 to the 3'-untranslated region of cardiomyocyte SERCA2a mRNA. Am. J. Physiol. Heart Circ. Physiol. 289: H2543-H2550 [Abstract] [Full Text]  
  • Jeyaraj, S., Dakhlallah, D., Hill, S. R., Lee, B. S. (2005). HuR Stabilizes Vacuolar H+-translocating ATPase mRNA during Cellular Energy Depletion. J. Biol. Chem. 280: 37957-37964 [Abstract] [Full Text]  
  • Fan, J., Heller, N. M., Gorospe, M., Atasoy, U., Stellato, C. (2005). The role of post-transcriptional regulation in chemokine gene expression in inflammation and allergy. Eur Respir J 26: 933-947 [Abstract] [Full Text]  
  • Pan, Y.-X., Chen, H., Kilberg, M. S. (2005). Interaction of RNA-binding Proteins HuR and AUF1 with the Human ATF3 mRNA 3'-Untranslated Region Regulates Its Amino Acid Limitation-induced Stabilization. J. Biol. Chem. 280: 34609-34616 [Abstract] [Full Text]  
  • Novotny, M., Datta, S., Biswas, R., Hamilton, T. (2005). Functionally Independent AU-rich Sequence Motifs Regulate KC (CXCL1) mRNA. J. Biol. Chem. 280: 30166-30174 [Abstract] [Full Text]  
  • Fialcowitz, E. J., Brewer, B. Y., Keenan, B. P., Wilson, G. M. (2005). A Hairpin-like Structure within an AU-rich mRNA-destabilizing Element Regulates trans-Factor Binding Selectivity and mRNA Decay Kinetics. J. Biol. Chem. 280: 22406-22417 [Abstract] [Full Text]  
  • Meng, Z., King, P. H., Nabors, L. B., Jackson, N. L., Chen, C.-Y., Emanuel, P. D., Blume, S. W. (2005). The ELAV RNA-stability factor HuR binds the 5'-untranslated region of the human IGF-IR transcript and differentially represses cap-dependent and IRES-mediated translation. Nucleic Acids Res 33: 2962-2979 [Abstract] [Full Text]  
  • Yamazaki, S., Muta, T., Matsuo, S., Takeshige, K. (2005). Stimulus-specific Induction of a Novel Nuclear Factor-{kappa}B Regulator, I{kappa}B-{zeta}, via Toll/Interleukin-1 Receptor Is Mediated by mRNA Stabilization. J. Biol. Chem. 280: 1678-1687 [Abstract] [Full Text]  
  • Seko, Y., Azmi, H., Fariss, R., Ragheb, J. A. (2004). Selective Cytoplasmic Translocation of HuR and Site-specific Binding to the Interleukin-2 mRNA Are Not Sufficient for CD28-mediated Stabilization of the mRNA. J. Biol. Chem. 279: 33359-33367 [Abstract] [Full Text]  
  • Ma, P., Cui, X., Wang, S., Zhang, J., Nishanian, E. V., Wang, W., Wesley, R. A., Danner, R. L. (2004). Nitric oxide post-transcriptionally up-regulates LPS-induced IL-8 expression through p38 MAPK activation. J. Leukoc. Biol. 76: 278-287 [Abstract] [Full Text]  
  • Winzen, R., Gowrishankar, G., Bollig, F., Redich, N., Resch, K., Holtmann, H. (2004). Distinct Domains of AU-Rich Elements Exert Different Functions in mRNA Destabilization and Stabilization by p38 Mitogen-Activated Protein Kinase or HuR. Mol. Cell. Biol. 24: 4835-4847 [Abstract] [Full Text]  
  • CHEN, C.-Y. A., XU, N., ZHU, W., SHYU, A.-B. (2004). Functional dissection of hnRNP D suggests that nuclear import is required before hnRNP D can modulate mRNA turnover in the cytoplasm. RNA 10: 669-680 [Abstract] [Full Text]  
  • Yasuda, S., Wada, S., Arao, Y., Kogawa, M., Kayama, F., Katayama, S. (2004). Interaction between 3' Untranslated Region of Calcitonin Receptor Messenger Ribonucleic Acid (RNA) and Adenylate/Uridylate (AU)-Rich Element Binding Proteins (AU-Rich RNA-Binding Factor 1 and Hu Antigen R). Endocrinology 145: 1730-1738 [Abstract] [Full Text]  
  • de Silanes, I. L., Zhan, M., Lal, A., Yang, X., Gorospe, M. (2004). Identification of a target RNA motif for RNA-binding protein HuR. Proc. Natl. Acad. Sci. USA 101: 2987-2992 [Abstract] [Full Text]  
  • Aoki, K., Matsumoto, K., Tsujimoto, M. (2003). Xenopus Cold-inducible RNA-binding Protein 2 Interacts with ElrA, the Xenopus Homolog of HuR, and Inhibits Deadenylation of Specific mRNAs. J. Biol. Chem. 278: 48491-48497 [Abstract] [Full Text]  
  • Adams, D. J., Beveridge, D. J., van der Weyden, L., Mangs, H., Leedman, P. J., Morris, B. J. (2003). HADHB, HuR, and CP1 Bind to the Distal 3'-Untranslated Region of Human Renin mRNA and Differentially Modulate Renin Expression. J. Biol. Chem. 278: 44894-44903 [Abstract] [Full Text]  
  • Park-Lee, S., Kim, S., Laird-Offringa, I. A. (2003). Characterization of the Interaction between Neuronal RNA-binding Protein HuD and AU-rich RNA. J. Biol. Chem. 278: 39801-39808 [Abstract] [Full Text]  
  • Schroeder, J. M., Liu, W., Curthoys, N. P. (2003). pH-responsive stabilization of glutamate dehydrogenase mRNA in LLC-PK1-F+ cells. Am. J. Physiol. Renal Physiol. 285: F258-F265 [Abstract] [Full Text]  
  • Biswas, R., Datta, S., Gupta, J. D., Novotny, M., Tebo, J., Hamilton, T. A. (2003). Regulation of Chemokine mRNA Stability by Lipopolysaccharide and IL-10. J. Immunol. 170: 6202-6208 [Abstract] [Full Text]  
  • De Gaudenzi, J. G., D'Orso, I., Frasch, A. C. C. (2003). RNA Recognition Motif-type RNA-binding Proteins in Trypanosoma cruzi Form a Family Involved in the Interaction with Specific Transcripts in Vivo. J. Biol. Chem. 278: 18884-18894 [Abstract] [Full Text]  
  • Tebo, J., Der, S., Frevel, M., Khabar, K. S. A., Williams, B. R. G., Hamilton, T. A. (2003). Heterogeneity in Control of mRNA Stability by AU-rich Elements. J. Biol. Chem. 278: 12085-12093 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»