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 Kasper, L. H.
Right arrow Articles by van Deursen, J. M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kasper, L. H.
Right arrow Articles by van Deursen, J. M. A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, January 1999, p. 764-776, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

CREB Binding Protein Interacts with Nucleoporin-Specific FG Repeats That Activate Transcription and Mediate NUP98-HOXA9 Oncogenicity

Lawryn H. Kasper,1 Paul K. Brindle,2 Catherine A. Schnabel,3 Colin E. J. Pritchard,1 Michael L. Cleary,3 and Jan M. A. van Deursen1,*

Departments of Genetics1 and Biochemistry,2 St. Jude Children's Research Hospital, Memphis, Tennessee 38105, and Department of Pathology, Stanford University, Stanford, California 943053

Received 14 August 1998/Returned for modification 8 September 1998/Accepted 29 September 1998

Genes encoding the Phe-Gly (FG) repeat-containing nucleoporins NUP98 and CAN/NUP214 are at the breakpoints of several chromosomal translocations associated with human acute myeloid leukemia (AML), but their role in oncogenesis is unclear. Here we demonstrate that the NUP98-HOXA9 fusion gene encodes two nuclear oncoproteins with either 19 or 37 NUP98 FG repeats fused to the DNA binding and PBX heterodimerization domains of the transcription factor HOXA9. Both NUP98-HOXA9 chimeras transformed NIH 3T3 fibroblasts, and this transformation required the HOXA9 domains for DNA binding and PBX interaction. Surprisingly, the FG repeats acted as very potent transactivators of gene transcription. This NUP98-derived activity is essential for transformation and can be replaced by the bona fide transactivation domain of VP16. Interestingly, FG repeat-containing segments derived from the nucleoporins NUP153 and CAN/NUP214 functioned similarly to those from NUP98. We further demonstrate that transactivation by FG repeat-rich segments of NUP98 correlates with their ability to interact functionally and physically with the transcriptional coactivators CREB binding protein (CBP) and p300. This finding shows, for the first time, that a translocation-generated fusion protein appears to recruit CBP/p300 as an important step of its oncogenic mechanism. Together, our results suggest that NUP98-HOXA9 chimeras are aberrant transcription factors that deregulate HOX-responsive genes through the transcriptional activation properties of nucleoporin-specific FG repeats that recruit CBP/p300. Indeed, FG repeat-mediated transactivation may be a shared pathogenic function of nucleoporins implicated human AML.

* Corresponding author. Present address: Mayo Clinic, 200 First St. SW, Rochester, MN 55905. Phone: (507) 266-4598. Fax: (507) 266-5201.

Molecular and Cellular Biology, January 1999, p. 764-776, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Jul-Larsen, A., Grudic, A., Bjerkvig, R., Ove Boe, S. (2009). Cell-cycle regulation and dynamics of cytoplasmic compartments containing the promyelocytic leukemia protein and nucleoporins. J. Cell Sci. 122: 1201-1210 [Abstract] [Full Text]  
  • Gorello, P., Brandimarte, L., La Starza, R., Pierini, V., Bury, L., Rosati, R., Martelli, M. F., Vandenberghe, P., Wlodarska, I., Mecucci, C. (2008). t(3;11)(q12;p15)/NUP98-LOC348801 fusion transcript in acute myeloid leukemia. haematol 93: 1398-1401 [Abstract] [Full Text]  
  • Jankovic, D., Gorello, P., Liu, T., Ehret, S., La Starza, R., Desjobert, C., Baty, F., Brutsche, M., Jayaraman, P.-S., Santoro, A., Mecucci, C., Schwaller, J. (2008). Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia. Blood 111: 5672-5682 [Abstract] [Full Text]  
  • Strehl, S., Nebral, K., Konig, M., Harbott, J., Strobl, H., Ratei, R., Struski, S., Bielorai, B., Lessard, M., Zimmermann, M., Haas, O. A., Izraeli, S. (2008). ETV6-NCOA2: A Novel Fusion Gene in Acute Leukemia Associated with Coexpression of T-Lymphoid and Myeloid Markers and Frequent NOTCH1 Mutations. Clin. Cancer Res. 14: 977-983 [Abstract] [Full Text]  
  • Jeganathan, K., Malureanu, L., Baker, D. J., Abraham, S. C., van Deursen, J. M. (2007). Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis. JCB 179: 255-267 [Abstract] [Full Text]  
  • Matsumoto, T., Baker, D. J., d'Uscio, L. V., Mozammel, G., Katusic, Z. S., van Deursen, J. M. (2007). Aging-Associated Vascular Phenotype in Mutant Mice With Low Levels of BubR1. Stroke 38: 1050-1056 [Abstract] [Full Text]  
  • Lindsey, S., Huang, W., Wang, H., Horvath, E., Zhu, C., Eklund, E. A. (2007). Activation of SHP2 Protein-tyrosine Phosphatase Increases HoxA10-induced Repression of the Genes Encoding gp91PHOX and p67PHOX. J. Biol. Chem. 282: 2237-2249 [Abstract] [Full Text]  
  • Chung, K. Y., Morrone, G., Schuringa, J. J., Plasilova, M., Shieh, J.-H., Zhang, Y., Zhou, P., Moore, M. A.S. (2006). Enforced Expression of NUP98-HOXA9 in Human CD34+ Cells Enhances Stem Cell Proliferation. Cancer Res. 66: 11781-11791 [Abstract] [Full Text]  
  • Camos, M., Esteve, J., Jares, P., Colomer, D., Rozman, M., Villamor, N., Costa, D., Carrio, A., Nomdedeu, J., Montserrat, E., Campo, E. (2006). Gene Expression Profiling of Acute Myeloid Leukemia with Translocation t(8;16)(p11;p13) and MYST3-CREBBP Rearrangement Reveals a Distinctive Signature with a Specific Pattern of HOX Gene Expression.. Cancer Res. 66: 6947-6954 [Abstract] [Full Text]  
  • Takeda, A., Goolsby, C., Yaseen, N. R. (2006). NUP98-HOXA9 Induces Long-term Proliferation and Blocks Differentiation of Primary Human CD34+ Hematopoietic Cells.. Cancer Res. 66: 6628-6637 [Abstract] [Full Text]  
  • Bai, X.-T., Gu, B.-W., Yin, T., Niu, C., Xi, X.-D., Zhang, J., Chen, Z., Chen, S.-J. (2006). Trans-Repressive Effect of NUP98-PMX1 on PMX1-Regulated c-FOS Gene through Recruitment of Histone Deacetylase 1 by FG Repeats.. Cancer Res. 66: 4584-4590 [Abstract] [Full Text]  
  • Santangelo, G. M. (2006). Glucose Signaling in Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev. 70: 253-282 [Abstract] [Full Text]  
  • Baker, D. J., Jeganathan, K. B., Malureanu, L., Perez-Terzic, C., Terzic, A., van Deursen, J. M.A. (2006). Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice.. JCB 172: 529-540 [Abstract] [Full Text]  
  • Kasper, L. H., Fukuyama, T., Biesen, M. A., Boussouar, F., Tong, C., de Pauw, A., Murray, P. J., van Deursen, J. M. A., Brindle, P. K. (2006). Conditional Knockout Mice Reveal Distinct Functions for the Global Transcriptional Coactivators CBP and p300 in T-Cell Development. Mol. Cell. Biol. 26: 789-809 [Abstract] [Full Text]  
  • Nebral, K., Schmidt, H. H., Haas, O. A., Strehl, S. (2005). NUP98 Is Fused to Topoisomerase (DNA) II{beta} 180 kDa (TOP2B) in a Patient with Acute Myeloid Leukemia with a New t(3;11)(p24;p15). Clin. Cancer Res. 11: 6489-6494 [Abstract] [Full Text]  
  • Menon, B. B., Sarma, N. J., Pasula, S., Deminoff, S. J., Willis, K. A., Barbara, K. E., Andrews, B., Santangelo, G. M. (2005). Reverse recruitment: The Nup84 nuclear pore subcomplex mediates Rap1/Gcr1/Gcr2 transcriptional activation. Proc. Natl. Acad. Sci. USA 102: 5749-5754 [Abstract] [Full Text]  
  • Kindle, K. B., Troke, P. J. F., Collins, H. M., Matsuda, S., Bossi, D., Bellodi, C., Kalkhoven, E., Salomoni, P., Pelicci, P. G., Minucci, S., Heery, D. M. (2005). MOZ-TIF2 Inhibits Transcription by Nuclear Receptors and p53 by Impairment of CBP Function. Mol. Cell. Biol. 25: 988-1002 [Abstract] [Full Text]  
  • Iwasaki, M., Kuwata, T., Yamazaki, Y., Jenkins, N. A., Copeland, N. G., Osato, M., Ito, Y., Kroon, E., Sauvageau, G., Nakamura, T. (2005). Identification of cooperative genes for NUP98-HOXA9 in myeloid leukemogenesis using a mouse model. Blood 105: 784-793 [Abstract] [Full Text]  
  • Beslu, N., Krosl, J., Laurin, M., Mayotte, N., Humphries, K. R., Sauvageau, G. (2004). Molecular interactions involved in HOXB4-induced activation of HSC self-renewal. Blood 104: 2307-2314 [Abstract] [Full Text]  
  • Gurevich, R. M., Aplan, P. D., Humphries, R. K. (2004). NUP98-Topoisomerase I acute myeloid leukemia-associated fusion gene has potent leukemogenic activities independent of an engineered catalytic site mutation. Blood 104: 1127-1136 [Abstract] [Full Text]  
  • Griffis, E. R., Craige, B., Dimaano, C., Ullman, K. S., Powers, M. A. (2004). Distinct Functional Domains within Nucleoporins Nup153 and Nup98 Mediate Transcription-dependent Mobility. Mol. Biol. Cell 15: 1991-2002 [Abstract] [Full Text]  
  • Bernad, R., van der Velde, H., Fornerod, M., Pickersgill, H. (2004). Nup358/RanBP2 Attaches to the Nuclear Pore Complex via Association with Nup88 and Nup214/CAN and Plays a Supporting Role in CRM1-Mediated Nuclear Protein Export. Mol. Cell. Biol. 24: 2373-2384 [Abstract] [Full Text]  
  • Pineault, N., Abramovich, C., Ohta, H., Humphries, R. K. (2004). Differential and Common Leukemogenic Potentials of Multiple NUP98-Hox Fusion Proteins Alone or with Meis1. Mol. Cell. Biol. 24: 1907-1917 [Abstract] [Full Text]  
  • Oki, M., Valenzuela, L., Chiba, T., Ito, T., Kamakaka, R. T. (2004). Barrier Proteins Remodel and Modify Chromatin To Restrict Silenced Domains. Mol. Cell. Biol. 24: 1956-1967 [Abstract] [Full Text]  
  • Ghannam, G., Takeda, A., Camarata, T., Moore, M. A., Viale, A., Yaseen, N. R. (2004). The Oncogene Nup98-HOXA9 Induces Gene Transcription in Myeloid Cells. J. Biol. Chem. 279: 866-875 [Abstract] [Full Text]  
  • Lu, Y., Goldenberg, I., Bei, L., Andrejic, J., Eklund, E. A. (2003). HoxA10 Represses Gene Transcription in Undifferentiated Myeloid Cells by Interaction with Histone Deacetylase 2. J. Biol. Chem. 278: 47792-47802 [Abstract] [Full Text]  
  • Pineault, N., Buske, C., Feuring-Buske, M., Abramovich, C., Rosten, P., Hogge, D. E., Aplan, P. D., Humphries, R. K. (2003). Induction of acute myeloid leukemia in mice by the human leukemia-specific fusion gene NUP98-HOXD13 in concert with Meis1. Blood 101: 4529-4538 [Abstract] [Full Text]  
  • Wu, X., Platt, J. L., Cascalho, M. (2003). Dimerization of MLH1 and PMS2 Limits Nuclear Localization of MutL{alpha}. Mol. Cell. Biol. 23: 3320-3328 [Abstract] [Full Text]  
  • Barbouti, A., Hoglund, M., Johansson, B., Lassen, C., Nilsson, P.-G., Hagemeijer, A., Mitelman, F., Fioretos, T. (2003). A Novel Gene, MSI2, Encoding a Putative RNA-binding Protein Is Recurrently Rearranged at Disease Progression of Chronic Myeloid Leukemia and Forms a Fusion Gene with HOXA9 as a Result of the Cryptic t(7;17)(p15;q23). Cancer Res. 63: 1202-1206 [Abstract] [Full Text]  
  • Babu, J. R., Jeganathan, K. B., Baker, D. J., Wu, X., Kang-Decker, N., van Deursen, J. M. (2003). Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation. JCB 160: 341-353 [Abstract] [Full Text]  
  • Rosati, R., La Starza, R., Veronese, A., Aventin, A., Schwienbacher, C., Vallespi, T., Negrini, M., Martelli, M. F., Mecucci, C. (2002). NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t(8;11)(p11.2;p15). Blood 99: 3857-3860 [Abstract] [Full Text]  
  • Fujino, T., Suzuki, A., Ito, Y., Ohyashiki, K., Hatano, Y., Miura, I., Nakamura, T. (2002). Single-translocation and double-chimeric transcripts: detection of NUP98-HOXA9 in myeloid leukemias with HOXA11 or HOXA13 breaks of the chromosomal translocation t(7;11)(p15;p15). Blood 99: 1428-1433 [Abstract] [Full Text]  
  • Hussey, D. J., Dobrovic, A. (2002). Recurrent coiled-coil motifs in NUP98 fusion partners provide a clue to leukemogenesis. Blood 99: 1097-1097 [Full Text]  
  • Sykes, D. B., Kamps, M. P. (2001). Estrogen-dependent E2a/Pbx1 myeloid cell lines exhibit conditional differentiation that can be arrested by other leukemic oncoproteins. Blood 98: 2308-2318 [Abstract] [Full Text]  
  • Wu, X., Kasper, L. H., Mantcheva, R. T., Mantchev, G. T., Springett, M. J., van Deursen, J. M. A. (2001). Disruption of the FG nucleoporin NUP98 causes selective changes in nuclear pore complex stoichiometry and function. Proc. Natl. Acad. Sci. USA 98: 3191-3196 [Abstract] [Full Text]  
  • Fontoura, B. M. A., Dales, S., Blobel, G., Zhong, H. (2001). The nucleoporin Nup98 associates with the intranuclear filamentous protein network of TPR. Proc. Natl. Acad. Sci. USA 98: 3208-3213 [Abstract] [Full Text]  
  • Ahuja, H. G., Hong, J., Aplan, P. D., Tcheurekdjian, L., Forman, S. J., Slovak, M. L. (2000). t(9;11)(p22;p15) in Acute Myeloid Leukemia Results in a Fusion between NUP98 and the Gene Encoding Transcriptional Coactivators p52 and p75-Lens Epithelium-derived Growth Factor (LEDGF). Cancer Res. 60: 6227-6229 [Abstract] [Full Text]  
  • Goodman, R. H., Smolik, S. (2000). CBP/p300 in cell growth, transformation, and development. Genes Dev. 14: 1553-1577 [Full Text]  
  • Compagnone, N. A., Zhang, P., Vigne, J.-L., Mellon, S. H. (2000). Novel Role for the Nuclear Phosphoprotein SET in Transcriptional Activation of P450c17 and Initiation of Neurosteroidogenesis. Mol. Endocrinol. 14: 875-888 [Abstract] [Full Text]  
  • Calvo, K. R., Sykes, D. B., Pasillas, M., Kamps, M. P. (2000). Hoxa9 Immortalizes a Granulocyte-Macrophage Colony-Stimulating Factor-Dependent Promyelocyte Capable of Biphenotypic Differentiation to Neutrophils or Macrophages, Independent of Enforced Meis Expression. Mol. Cell. Biol. 20: 3274-3285 [Abstract] [Full Text]  
  • Ahuja, H. G., Felix, C. A., Aplan, P. D. (1999). The t(11;20)(p15;q11) Chromosomal Translocation Associated With Therapy-Related Myelodysplastic Syndrome Results in an NUP98-TOP1 Fusion. Blood 94: 3258-3261 [Abstract] [Full Text]  
  • Rosenblum, J. S., Blobel, G. (1999). Autoproteolysis in nucleoporin biogenesis. Proc. Natl. Acad. Sci. USA 96: 11370-11375 [Abstract] [Full Text]  
  • Hussey, D. J., Nicola, M., Moore, S., Peters, G. B., Dobrovic, A. (1999). The (4;11)(q21;p15) Translocation Fuses the NUP98 and RAP1GDS1 Genes and Is Recurrent in T-Cell Acute Lymphocytic Leukemia. Blood 94: 2072-2079 [Abstract] [Full Text]  
  • Parker, D., Rivera, M., Zor, T., Henrion-Caude, A., Radhakrishnan, I., Kumar, A., Shapiro, L. H., Wright, P. E., Montminy, M., Brindle, P. K. (1999). Role of Secondary Structure in Discrimination between Constitutive and Inducible Activators. Mol. Cell. Biol. 19: 5601-5607 [Abstract] [Full Text]  
  • Nakamura, T., Yamazaki, Y., Hatano, Y., Miura, I. (1999). NUP98 Is Fused to PMX1 Homeobox Gene in Human Acute Myelogenous Leukemia With Chromosome Translocation t(1;11)(q23;p15). Blood 94: 741-747 [Abstract] [Full Text]  
  • Pritchard, C. E.J., Fornerod, M., Kasper, L. H., van Deursen, J. M.A. (1999). RAE1 Is a Shuttling mRNA Export Factor That Binds to a GLEBS-like NUP98 Motif at the Nuclear Pore Complex through Multiple Domains. JCB 145: 237-254 [Abstract] [Full Text]  
  • Wang, X., Babu, J. R., Harden, J. M., Jablonski, S. A., Gazi, M. H., Lingle, W. L., de Groen, P. C., Yen, T. J., van Deursen, J. M. A. (2001). The Mitotic Checkpoint Protein hBUB3 and the mRNA Export Factor hRAE1 Interact with GLE2p-binding Sequence (GLEBS)-containing Proteins. J. Biol. Chem. 276: 26559-26567 [Abstract] [Full Text]  
  • Griffis, E. R., Altan, N., Lippincott-Schwartz, J., Powers, M. A. (2002). Nup98 Is a Mobile Nucleoporin with Transcription-dependent Dynamics. Mol. Biol. Cell 13: 1282-1297 [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»