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J. Biol. Chem., Vol. 280, Issue 26, 24642-24648, July 1, 2005

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Identification and Characterization of Novel Isoforms of Human DP-1

DP-1 REGULATES THE TRANSCRIPTIONAL ACTIVITY OF E2F1 AS WELL AS CELL CYCLE PROGRESSION IN A DOMINANT-NEGATIVE MANNER^*

Hironori Ishida, Yoshikazu Masuhiro, Akie Fukushima, Jose Guillermo Martinez Argueta, Noboru Yamaguchi, Susumu Shiota, and Shigemasa Hanazawa¶

From the Division of Oral Infectious Diseases and Immunology, Faculty of Dental Science, Kyushu University, Higashiku, Fukuoka, 812-8582 and the Department of Preventive Dentistry, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan

The cell cycle-regulating transcription factors DP-1 and E2F form a heterodimeric complex and play a central role in cell cycle progression. Two different DP subunits (DP-1 and DP-2) exist in humans. In this study, we identified two novel DP-1 isoforms (DP-1 and DP-1) and characterized their structure and function. DP-1 is composed of 278 amino acids and lacks a portion of the C-terminal heterodimerization domain, whereas DP-1 is composed of 357 amino acids with a frameshift that causes truncation of the C-terminal domain. Yeast two-hybrid and immunoprecipitation assays demonstrated that DP-1 binding to E2F1 was significantly reduced as compared with that of wild-type DP-1 or DP-1. Immunofluorescence analysis revealed that the subcellular localization of both DP-1 isoforms changed from the cytoplasm to the nucleus in HEK 293 cells cotransfected with E2F1 and wild-type DP-1 or DP-1. However, such a translocation for DP-1 was barely observed. Reverse transcription-PCR results showed that the three DP-1 isoforms are expressed ubiquitously at equal levels in several normal human tissues. We also demonstrated the expression of these isoforms at the protein level by Western blotting. Interestingly, we observed a significant decrease in transcriptional activity, a marked delay of cell cycle progression, and an inhibition of cell proliferation in DP-1-transfected HEK 293 cells. Together, the results of the present study suggest that DP-1 is a novel isoform of DP-1 that acts as a dominant-negative regulator of cell cycle progression.

Received for publication, January 6, 2005 , and in revised form, April 26, 2005.

^* This work was supported by the OSAKA Cancer Research Foundation. 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.

^¶ To whom correspondence should be addressed: Dept. of Applied Biological Sciences, College of Bioresource Science, Nihon University, Kameino, Fujisawa-City, Kanagawa 292-8510, Japan. Tel.: 81-466-84-3701. E-mail: hanazawa{at}brs.nihon-u.ac.jp.

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