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J. Biol. Chem., Vol. 283, Issue 27, 18753-18764, July 4, 2008

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A Novel Binding Factor of 14-3-3β Functions as a Transcriptional Repressor and Promotes Anchorage-independent Growth, Tumorigenicity, and Metastasis^*

From the Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Yamazaki 2641, Noda-shi, Chiba 278-8510, Japan

The 14-3-3 proteins form a highly conserved family of dimeric proteins that interact with various signal transduction proteins and regulate cell cycle, apoptosis, stress response, and malignant transformation. We previously demonstrated that the β isoform of 14-3-3 proteins promotes tumorigenicity and angiogenesis of rat hepatoma K2 cells. In this study, to analyze the mechanism of 14-3-3β-induced malignant transformation, yeast two-hybrid screening was performed, and a novel 14-3-3β-binding factor, FBI1 (fourteen-three-three beta interactant 1), was identified. In vitro binding and co-immunoprecipitation analyses verified specific interaction of 14-3-3β with FBI1. The strong expression of FBI1 was observed in several tumor cell lines but not in non-tumor cell lines. Forced expression of antisense FBI1 in K2 cells inhibited anchorage-independent growth but had no significant effect on cell proliferation in monolayer culture. Down-regulation of FBI1 also inhibited tumorigenicity and metastasis accompanying a decrease in MMP-9 (matrix metalloproteinase-9) expression. In addition, the duration of ERK1/2 activation was curtailed in antisense FBI1-expressing K2 cells. A luciferase reporter assay revealed that the FBI1-14-3-3β complex could act as a transcriptional silencer, and MKP-1 (MAPK phosphatase-1) was one of the target genes of the FBI1-14-3-3β complex. Moreover, chromatin immunoprecipitation analysis demonstrated that FBI1 and 14-3-3β were presented on the MKP-1 promoter. These results indicate that FBI1 promotes sustained ERK1/2 activation through repression of MKP-1 transcription, resulting in promotion of tumorigenicity and metastasis.

Received for publication, April 1, 2008

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AB234867.

^* This work was partially supported by the "Academic Frontier" project for private universities and matching fund subsidy from MEXT (Ministry of Education, Culture, Sports, Science, and Technology) Grant 2006-2010 (to F. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 81-4-7124-1501; Fax: 81-4-7125-1841; E-mail: ftashir{at}rs.noda.tus.ac.jp.

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