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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.


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