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J. Biol. Chem., Vol. 280, Issue 48, 39827-39834, December 2, 2005

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Nuclear Factor 1 Family Members Interact with Hepatocyte Nuclear Factor 1 to Synergistically Activate L-type Pyruvate Kinase Gene Transcription^*

Shin-ichi Satoh, Takashi Noaki, Tatsuya Ishigure, Shigehiro Osada, Masayoshi Imagawa, Naoyuki Miura¶, Kazuya Yamada||, and Tamio Noguchi1

From the Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa-ku, Nagoya 464-8601, Japan, Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya 467-8603, Japan, ^¶Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan, and ^||Department of Biochemistry, Faculty of Medical Sciences, University of Fukui, Matsuoka, Fukui 910-1193, Japan

Transcription of hepatic L-type pyruvate kinase (L-PK) gene is cell type-specific and is under the control of various nutritional conditions. The L-PK gene contains multiple cis-regulatory elements located within a 170-bp upstream region necessary for these regulations. These elements can synergistically stimulate L-PK gene transcription, although their mechanisms are largely unknown. Because nuclear factor (NF) 1 family members bind to specific cis-regulatory elements known as L-IIA and L-IIB and hepatocyte nuclear factor (HNF) 1 binds to the adjacent element L-I, we examined the functional and physical interactions between these two transcription factors. Reporter gene assay showed that these two factors synergistically activated the L-PK promoter containing the 5'-flanking region up to –189. Although two NF1-binding sites are required for the maximum synergistic effect of NF1 family members with HNF1, significant functional interaction between the two factors was observed in the L-PK promoter containing two mutated NF1-binding sites and also in the promoter containing only the HNF1-binding site, raising the possibility that NF1 proteins function as HNF1 co-activators. Chromatin immunoprecipitation assay revealed that both NF1 proteins and HNF1 bound to the promoter region of the L-PK gene in vivo. In vitro binding assay confirmed that NF1 proteins directly interacted mainly with the homeodomain of HNF1 via their DNA-binding domains. This interaction enhanced HNF1 binding to the L-I element and was also observed in rat liver by co-immunoprecipitation assay. Thus, we conclude that cooperative interaction between NF1 family members and HNF1 plays an important role in hepatic L-PK transcription.

Received for publication, July 6, 2005 , and in revised form, September 27, 2005.

^* This work was supported by a Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. 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: Dept. of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. Tel.: 81-52-789-4121; Fax: 81-52-789-4121; E-mail: tnoguchi{at}agr.nagoya-u.ac.jp.

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