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 Kanno, Y.
Right arrow Articles by Ito, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kanno, Y.
Right arrow Articles by Ito, Y.

 Previous Article  |  Next Article 

Mol Cell Biol, July 1998, p. 4252-4261, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Cytoplasmic Sequestration of the Polyomavirus Enhancer Binding Protein 2 (PEBP2)/Core Binding Factor alpha  (CBFalpha ) Subunit by the Leukemia-Related PEBP2/CBFbeta -SMMHC Fusion Protein Inhibits PEBP2/CBF-Mediated Transactivation

Yuka Kanno, Tomohiko Kanno, Chohei Sakakura, Suk-Chul Bae, and Yoshiaki Ito*

Department of Viral Oncology, Institute for Virus Research, Kyoto University, Kyoto 606, Japan

Received 4 March 1998/Returned for modification 7 April 1998/Accepted 21 April 1998

The polyomavirus enhancer binding protein 2 (PEBP2)/core binding factor (CBF) is a transcription factor composed of two subunits, alpha  and beta . The gene encoding the beta  subunit is disrupted by inv(16), resulting in the formation of a chimeric protein, beta -SMMHC, which is associated with acute myelogenous leukemia. To understand the effect of beta -SMMHC on PEBP2-mediated transactivation, we used a luciferase assay system in which contribution of both the alpha  and beta  subunits was absolutely required to activate transcription. Using this system, we found that the minimal region of the beta  subunit required for transactivation resides between amino acid 1 and 135, which is known to dimerize with the alpha  subunit. In contrast, beta -SMMHC, despite having this minimal region for dimerization and transactivation, failed to support transcription with the alpha  subunit. Furthermore beta -SMMHC blocked the synergistic transcription achieved by PEBP2 and CCAAT/enhancer binding protein alpha . By using a construct in which the PEBP2 alpha  subunit was fused to the glucocorticoid receptor ligand binding domain, we demonstrated that coexpressed beta -SMMHC tightly sequestered the alpha  subunit in the cytoplasm and blocked dexamethasone-dependent nuclear translocation of the alpha  subunit. Thus, the result suggess that beta -SMMHC inhibits PEBP2-mediated transcription via cytoplasmic sequestration of the alpha  subunit. Lastly proliferation of ME-1 cells that harbor inv(16) was blocked by an antisense oligonucleotide complementary to the junction of the chimeric mRNA, suggesting that beta -SMMHC contributes to leukemogenesis by blocking the differentiation of myeloid cells.

* Corresponding author. Mailing address: Institute for Virus Research, Kyoto University, Shogo-in, Sakyo-ku, Kyoto 606, Japan. Phone: 81-75-751-4028. Fax: 81-75-752-3232. E-mail: yito{at}virus.kyoto-u.ac.jp.

Mol Cell Biol, July 1998, p. 4252-4261, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Wee, H.-J., Voon, D. C.-C., Bae, S.-C., Ito, Y. (2008). PEBP2-{beta}/CBF-{beta}-dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis. Blood 112: 3777-3787 [Abstract] [Full Text]  
  • Markus, J., Garin, M. T., Bies, J., Galili, N., Raza, A., Thirman, M. J., Le Beau, M. M., Rowley, J. D., Liu, P. P., Wolff, L. (2007). Methylation-Independent Silencing of the Tumor Suppressor INK4b (p15) by CBF{beta}-SMMHC in Acute Myelogenous Leukemia with inv(16). Cancer Res. 67: 992-1000 [Abstract] [Full Text]  
  • Frohling, S., Scholl, C., Gilliland, D. G., Levine, R. L. (2005). Genetics of Myeloid Malignancies: Pathogenetic and Clinical Implications. JCO 23: 6285-6295 [Abstract] [Full Text]  
  • Helbling, D., Mueller, B. U., Timchenko, N. A., Schardt, J., Eyer, M., Betts, D. R., Jotterand, M., Meyer-Monard, S., Fey, M. F., Pabst, T. (2005). CBFB-SMMHC is correlated with increased calreticulin expression and suppresses the granulocytic differentiation factor CEBPA in AML with inv(16). Blood 106: 1369-1375 [Abstract] [Full Text]  
  • Yang, G., Khalaf, W., van de Locht, L., Jansen, J. H., Gao, M., Thompson, M. A., van der Reijden, B. A., Gutmann, D. H., Delwel, R., Clapp, D. W., Hiebert, S. W. (2005). Transcriptional Repression of the Neurofibromatosis-1 Tumor Suppressor by the t(8;21) Fusion Protein. Mol. Cell. Biol. 25: 5869-5879 [Abstract] [Full Text]  
  • Huang, G., Shigesada, K., Wee, H.-J., Liu, P. P., Osato, M., Ito, Y. (2004). Molecular basis for a dominant inactivation of RUNX1/AML1 by the leukemogenic inversion 16 chimera. Blood 103: 3200-3207 [Abstract] [Full Text]  
  • Harada, H., Harada, Y., Niimi, H., Kyo, T., Kimura, A., Inaba, T. (2004). High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. Blood 103: 2316-2324 [Abstract] [Full Text]  
  • Durst, K. L., Lutterbach, B., Kummalue, T., Friedman, A. D., Hiebert, S. W. (2003). The inv(16) Fusion Protein Associates with Corepressors via a Smooth Muscle Myosin Heavy-Chain Domain. Mol. Cell. Biol. 23: 607-619 [Abstract] [Full Text]  
  • Kummalue, T., Lou, J., Friedman, A. D. (2002). Multimerization via Its Myosin Domain Facilitates Nuclear Localization and Inhibition of Core Binding Factor (CBF) Activities by the CBF{beta}-Smooth Muscle Myosin Heavy Chain Myeloid Leukemia Oncoprotein. Mol. Cell. Biol. 22: 8278-8291 [Abstract] [Full Text]  
  • Kundu, M., Chen, A., Anderson, S., Kirby, M., Xu, L., Castilla, L. H., Bodine, D., Liu, P. P. (2002). Role of Cbfb in hematopoiesis and perturbations resulting from expression of the leukemogenic fusion gene Cbfb-MYH11. Blood 100: 2449-2456 [Abstract] [Full Text]  
  • Michaud, J., Wu, F., Osato, M., Cottles, G. M., Yanagida, M., Asou, N., Shigesada, K., Ito, Y., Benson, K. F., Raskind, W. H., Rossier, C., Antonarakis, S. E., Israels, S., McNicol, A., Weiss, H., Horwitz, M., Scott, H. S. (2002). In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Blood 99: 1364-1372 [Abstract] [Full Text]  
  • Kaminker, J. S., Singh, R., Lebestky, T., Yan, H., Banerjee, U. (2001). Redundant function of Runt Domain binding partners, Big brother and Brother, during Drosophila development. Development 128: 2639-2648 [Abstract] [Full Text]  
  • Miller, J. D., Stacy, T., Liu, P. P., Speck, N. A. (2001). Core-binding factor {beta} (CBF{beta}), but not CBF{beta}-smooth muscle myosin heavy chain, rescues definitive hematopoiesis in CBF{beta}-deficient embryonic stem cells. Blood 97: 2248-2256 [Abstract] [Full Text]  
  • Strom, D. K., Nip, J., Westendorf, J. J., Linggi, B., Lutterbach, B., Downing, J. R., Lenny, N., Hiebert, S. W. (2000). Expression of the AML-1 Oncogene Shortens the G1 Phase of the Cell Cycle. J. Biol. Chem. 275: 3438-3445 [Abstract] [Full Text]  
  • Lutterbach, B., Hou, Y., Durst, K. L., Hiebert, S. W. (1999). The inv(16) encodes an acute myeloid leukemia 1 transcriptional corepressor. Proc. Natl. Acad. Sci. USA 96: 12822-12827 [Abstract] [Full Text]  
  • Lowenberg, B., Downing, J. R., Burnett, A. (1999). Acute Myeloid Leukemia. NEJM 341: 1051-1062 [Full Text]  
  • Osato, M., Asou, N., Abdalla, E., Hoshino, K., Yamasaki, H., Okubo, T., Suzushima, H., Takatsuki, K., Kanno, T., Shigesada, K., Ito, Y. (1999). Biallelic and Heterozygous Point Mutations in the Runt Domain of the AML1/PEBP2alpha B Gene Associated With Myeloblastic Leukemias. Blood 93: 1817-1824 [Abstract] [Full Text]  
  • Li, L., Gergen, J. (1999). Differential interactions between Brother proteins and Runt domain proteins in the Drosophila embryo and eye. Development 126: 3313-3322 [Abstract]  
  • Kogan, S. C., Lagasse, E., Atwater, S., Bae, S.-c., Weissman, I., Ito, Y., Bishop, J. M. (1998). The PEBP2beta MYH11 fusion created by Inv(16)(p13;q22) in myeloid leukemia impairs neutrophil maturation and contributes to granulocytic dysplasia. Proc. Natl. Acad. Sci. USA 95: 11863-11868 [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»