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Abstract:

RSUME (RWD-containing SUMO Enhancer) is a small protein that increases SUMO conjugation to proteins. To date, four splice variants that codify three RSUME isoforms have been described, which differ in their C-terminal end. Comparing the structure of the RSUME isoforms we found that, in addition to the previously described RWD domain in the N-terminal, all these RSUME variants also contain an intermediate domain. Only the longest RSUME isoform presents a C-terminal domain that is absent in the others. Given these differences, we used the shortest and longest RSUME variants for comparative studies. We found that the C-terminal domain is dispensable for the SUMO-conjugation enhancer properties of RSUME. We also demonstrate that these two RSUME variants are equally induced by hypoxia. The NF-κB signaling pathway is inhibited and the HIF-1 pathway is increased more efficiently by the longest RSUME, by means of a greater physical interaction of RSUME267 with the target proteins. In addition, the mRNA and protein levels of these isoforms differ in human glioma samples; while the shortest RSUME isoform is expressed in all the tumors analyzed, the longest variant is expressed in most but not all of them. The results presented here show a degree of redundancy of the RSUME variants on the SUMO pathway. However, the increased inhibition conferred by RSUME267 over the NF-κB signaling pathway, the increased activation over the HIF-1 pathway and the different expression of the RSUME isoforms suggest specific roles for each RSUME isoform which may be relevant in certain types of brain tumors that express RSUME, like human pituitary adenomas and gliomas. © 2013 Gerez et al.

Registro:

Documento: Artículo
Título:In Silico Structural and Functional Characterization of the RSUME Splice Variants
Autor:Gerez, J.; Fuertes, M.; Tedesco, L.; Silberstein, S.; Sevlever, G.; Paez-Pereda, M.; Holsboer, F.; Turjanski, A.G.; Arzt, E.
Filiación:Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), CONICET- Partner Institute of the Max Planck Society, Buenos Aires, Argentina
Departamento de Fisiología y Biología Molecular, FCEN, Universidad de Buenos Aires, Buenos Aires, Argentina
Departamento de Neuropatología y Biología Molecular, FLENI, Buenos Aires, Argentina
Max Planck Institute of Psychiatry, Munich, Germany
Laboratorio de Bioinformática Estructural, Departamento de Química Biológica, INQUIMAE-CONICET, FCEN, Universidad de Buenos Aires, Buenos Aires, Argentina
Palabras clave:hypoxia inducible factor 1; immunoglobulin enhancer binding protein; messenger RNA; protein variant; regulator protein; RWD containing SUMO enhancer protein; SUMO protein; unclassified drug; hypoxia inducible factor 1; immunoglobulin enhancer binding protein; isoprotein; RSUME protein, human; SUMO 1 protein; transcription factor; article; brain cancer; carboxy terminal sequence; computer model; controlled study; gene expression; human; human tissue; molecular pathology; molecular weight; nucleotide sequence; protein domain; protein expression; protein function; protein processing; protein protein interaction; regulator gene; RWD containing SUMO enhancer gene; signal transduction; structure activity relation; structure analysis; amino acid sequence; animal; biology; cell line; chemical structure; chemistry; gene expression regulation; genetics; metabolism; molecular genetics; protein secondary structure; Amino Acid Sequence; Animals; Cell Line; Computational Biology; Gene Expression Regulation; Humans; Hypoxia-Inducible Factor 1; Models, Molecular; Molecular Sequence Data; NF-kappa B; Protein Isoforms; Protein Structure, Secondary; Signal Transduction; SUMO-1 Protein; Transcription Factors
Año:2013
Volumen:8
Número:2
DOI: http://dx.doi.org/10.1371/journal.pone.0057795
Título revista:PLoS ONE
Título revista abreviado:PLoS ONE
ISSN:19326203
CAS:SUMO 1 protein, 182213-10-1; Hypoxia-Inducible Factor 1; NF-kappa B; Protein Isoforms; RSUME protein, human; SUMO-1 Protein; Transcription Factors
PDF:https://bibliotecadigital.exactas.uba.ar/download/paper/paper_19326203_v8_n2_p_Gerez.pdf
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19326203_v8_n2_p_Gerez

Referencias:

  • Carbia-Nagashima, A., Gerez, J., Perez-Castro, C., Paez-Pereda, M., Silberstein, S., RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1alpha during hypoxia (2007) Cell, 131, pp. 309-323
  • Castro, C.P., Giacomini, D., Nagashima, A.C., Onofri, C., Graciarena, M., Reduced expression of the cytokine transducer gp130 inhibits hormone secretion, cell growth, and tumor development of pituitary lactosomatotrophic GH3 cells (2003) Endocrinology, 144, pp. 693-700
  • Frischmeyer, P.A., Dietz, H.C., Nonsense-mediated mRNA decay in health and disease (1999) Hum Mol Genet, 8, pp. 1893-1900
  • Hay, R.T., SUMO: a history of modification (2005) Mol Cell, 18, pp. 1-12
  • Geiss-Friedlander, R., Melchior, F., Concepts in sumoylation: a decade on (2007) Nat Rev Mol Cell Biol, 8, pp. 947-956
  • Doerks, T., Copley, R.R., Schultz, J., Ponting, C.P., Bork, P., Systematic identification of novel protein domain families associated with nuclear functions (2002) Genome Res, 12, pp. 47-56
  • Nameki, N., Yoneyama, M., Koshiba, S., Tochio, N., Inoue, M., Solution structure of the RWD domain of the mouse GCN2 protein (2004) Protein Sci, 13, pp. 2089-2100
  • Tong, H., Hateboer, G., Perrakis, A., Bernards, R., Sixma, T.K., Crystal structure of murine/human Ubc9 provides insight into the variability of the ubiquitin-conjugating system (1997) J Biol Chem, 272, pp. 21381-21387
  • Shan, B., Gerez, J., Haedo, M., Fuertes, M., Theodoropoulou, M., RSUME is implicated in HIF-1-induced VEGF-A production in pituitary tumour cells (2012) Endocr Relat Cancer, 19, pp. 13-27
  • Semenza, G.L., Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1 (1999) Annu Rev Cell Dev Biol, 15, pp. 551-578
  • Brahimi-Horn, M.C., Pouyssegur, J., HIF at a glance (2009) J Cell Sci, 122, pp. 1055-1057
  • Wang, G.L., Semenza, G.L., General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia (1993) Proc Natl Acad Sci U S A, 90, pp. 4304-4308
  • Fowkes, R.C., Vlotides, G., Hypoxia-induced VEGF production 'RSUMEs' in pituitary adenomas (2012) Endocr Relat Cancer, 19, pp. C1-C5
  • Hoffmann, E., Dittrich-Breiholz, O., Holtmann, H., Kracht, M., Multiple control of interleukin-8 gene expression (2002) J Leukoc Biol, 72, pp. 847-855
  • Berman, H., Henrick, K., Nakamura, H., Markley, J.L., The worldwide Protein Data Bank (wwPDB): ensuring a single, uniform archive of PDB data (2007) Nucleic Acids Res, 35, pp. D301-D303
  • McGuffin, L.J., Bryson, K., Jones, D.T., The PSIPRED protein structure prediction server (2000) Bioinformatics, 16, pp. 404-405
  • Ward, J.J., McGuffin, L.J., Bryson, K., Buxton, B.F., Jones, D.T., The DISOPRED server for the prediction of protein disorder (2004) Bioinformatics, 20, pp. 2138-2139
  • Kelley, L.A., Sternberg, M.J., Protein structure prediction on the Web: a case study using the Phyre server (2009) Nat Protoc, 4, pp. 363-371
  • Mount, D.W., Using the Basic Local Alignment Search Tool (BLAST) (2007) CSH Protoc 2007, , pdb top17
  • VanDemark, A.P., Hofmann, R.M., Tsui, C., Pickart, C.M., Wolberger, C., Molecular insights into polyubiquitin chain assembly: crystal structure of the Mms2/Ubc13 heterodimer (2001) Cell, 105, pp. 711-720
  • Kovalenko, O.V., Plug, A.W., Haaf, T., Gonda, D.K., Ashley, T., Mammalian ubiquitin-conjugating enzyme Ubc9 interacts with Rad51 recombination protein and localizes in synaptonemal complexes (1996) Proc Natl Acad Sci U S A, 93, pp. 2958-2963
  • Desterro, J.M., Rodriguez, M.S., Hay, R.T., SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation (1998) Mol Cell, 2, pp. 233-239
  • Melchior, F., Schergaut, M., Pichler, A., SUMO: ligases, isopeptidases and nuclear pores (2003) Trends Biochem Sci, 28, pp. 612-618
  • Pichler, A., Gast, A., Seeler, J.S., Dejean, A., Melchior, F., The nucleoporin RanBP2 has SUMO1 E3 ligase activity (2002) Cell, 108, pp. 109-120
  • Kotaja, N., Karvonen, U., Janne, O.A., Palvimo, J.J., PIAS proteins modulate transcription factors by functioning as SUMO-1 ligases (2002) Mol Cell Biol, 22, pp. 5222-5234
  • Kagey, M.H., Melhuish, T.A., Wotton, D., The polycomb protein Pc2 is a SUMO E3 (2003) Cell, 113, pp. 127-137
  • Hooft, R.W., Sander, C., Vriend, G., Positioning hydrogen atoms by optimizing hydrogen-bond networks in protein structures (1996) Proteins, 26, pp. 363-376
  • Eargle, J., Wright, D., Luthey-Schulten, Z., Multiple Alignment of protein structures and sequences for VMD (2006) Bioinformatics, 22, pp. 504-506
  • Humphrey, W., Dalke, A., Schulten, K., VMD: visual molecular dynamics (1996) J Mol Graph, 14, pp. 27-38
  • Stone, D.H., Research and the Internet (1998) J Public Health Med, 20, pp. 111-112
  • Laskowski, R.A., PDBsum new things (2009) Nucleic Acids Res, 37, pp. D355-D359
  • Kalli, K., Huntoon, C., Bell, M., McKean, D.J., Mechanism responsible for T-cell antigen receptor- and CD28- or interleukin 1 (IL-1) receptor-initiated regulation of IL-2 gene expression by NF-kappaB (1998) Mol Cell Biol, 18, pp. 3140-3148
  • Rodriguez, M.S., Dargemont, C., Hay, R.T., SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting (2001) J Biol Chem, 276, pp. 12654-12659
  • Tatham, M.H., Jaffray, E., Vaughan, O.A., Desterro, J.M., Botting, C.H., Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9 (2001) J Biol Chem, 276, pp. 35368-35374
  • Richard, D.E., Berra, E., Pouyssegur, J., Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells (2000) J Biol Chem, 275, pp. 26765-26771
  • Post, D.E., Van Meir, E.G., Generation of bidirectional hypoxia/HIF-responsive expression vectors to target gene expression to hypoxic cells (2001) Gene Ther, 8, pp. 1801-1807
  • Imamura, R., Konaka, K., Matsumoto, N., Hasegawa, M., Fukui, M., Fas ligand induces cell-autonomous NF-kappaB activation and interleukin-8 production by a mechanism distinct from that of tumor necrosis factor-alpha (2004) J Biol Chem, 279, pp. 46415-46423
  • Shima, D.T., Gougos, A., Miller, J.W., Tolentino, M., Robinson, G., Cloning and mRNA expression of vascular endothelial growth factor in ischemic retinas of Macaca fascicularis (1996) Invest Ophthalmol Vis Sci, 37, pp. 1334-1340
  • Rupprecht, R., Arriza, J.L., Spengler, D., Reul, J.M., Evans, R.M., Transactivation and synergistic properties of the mineralocorticoid receptor: relationship to the glucocorticoid receptor (1993) Mol Endocrinol, 7, pp. 597-603
  • Tanos, T., Marinissen, M.J., Leskow, F.C., Hochbaum, D., Martinetto, H., Phosphorylation of c-Fos by members of the p38 MAPK family. Role in the AP-1 response to UV light (2005) J Biol Chem, 280, pp. 18842-18852
  • Kovalovsky, D., Refojo, D., Liberman, A.C., Hochbaum, D., Pereda, M.P., Activation and induction of NUR77/NURR1 in corticotrophs by CRH/cAMP: involvement of calcium, protein kinase A, and MAPK pathways (2002) Mol Endocrinol, 16, pp. 1638-1651
  • Liberman, A.C., Refojo, D., Druker, J., Toscano, M., Rein, T., The activated glucocorticoid receptor inhibits the transcription factor T-bet by direct protein-protein interaction (2007) FASEB J, 21, pp. 1177-1188
  • Liberman, A.C., Druker, J., Refojo, D., Holsboer, F., Arzt, E., Glucocorticoids inhibit GATA-3 phosphorylation and activity in T cells (2009) FASEB J, 23, pp. 1558-1571
  • Paez-Pereda, M., Giacomini, D., Refojo, D., Nagashima, A.C., Hopfner, U., Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk (2003) Proc Natl Acad Sci U S A, 100, pp. 1034-1039
  • Ke, J., Liu, Y., Long, X., Li, J., Fang, W., Up-regulation of vascular endothelial growth factor in synovial fibroblasts from human temporomandibular joint by hypoxia (2007) J Oral Pathol Med, 36, pp. 290-296

Citas:

---------- APA ----------
Gerez, J., Fuertes, M., Tedesco, L., Silberstein, S., Sevlever, G., Paez-Pereda, M., Holsboer, F.,..., Arzt, E. (2013) . In Silico Structural and Functional Characterization of the RSUME Splice Variants. PLoS ONE, 8(2).
http://dx.doi.org/10.1371/journal.pone.0057795
---------- CHICAGO ----------
Gerez, J., Fuertes, M., Tedesco, L., Silberstein, S., Sevlever, G., Paez-Pereda, M., et al. "In Silico Structural and Functional Characterization of the RSUME Splice Variants" . PLoS ONE 8, no. 2 (2013).
http://dx.doi.org/10.1371/journal.pone.0057795
---------- MLA ----------
Gerez, J., Fuertes, M., Tedesco, L., Silberstein, S., Sevlever, G., Paez-Pereda, M., et al. "In Silico Structural and Functional Characterization of the RSUME Splice Variants" . PLoS ONE, vol. 8, no. 2, 2013.
http://dx.doi.org/10.1371/journal.pone.0057795
---------- VANCOUVER ----------
Gerez, J., Fuertes, M., Tedesco, L., Silberstein, S., Sevlever, G., Paez-Pereda, M., et al. In Silico Structural and Functional Characterization of the RSUME Splice Variants. PLoS ONE. 2013;8(2).
http://dx.doi.org/10.1371/journal.pone.0057795