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Molecular and Cellular Biology, December 1999, p. 8281-8291, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Identification of a Portable Repression Domain and an E1A-Responsive Activation Domain in Pax4: a Possible Role of Pax4 as a Transcriptional Repressor in the Pancreas

Yoshio Fujitani,1 Yoshitaka Kajimoto,1,* Tetsuyuki Yasuda,1 Taka-Aki Matsuoka,1 Hideaki Kaneto,1 Yutaka Umayahara,1 Noriko Fujita,1 Hirotaka Watada,1 Jun-Ichi Miyazaki,2 Yoshimitsu Yamasaki,1 and Masatsugu Hori1

Department of Internal Medicine and Therapeutics1 and Department of Nutrition and Physiological Chemistry,2 Osaka University Graduate School of Medicine, Suita 565-0871, Japan

Received 25 March 1999/Returned for modification 20 May 1999/Accepted 16 August 1999

Pax4 is a paired-domain (PD)-containing transcription factor which plays a crucial role in pancreatic beta /delta -cell development. In this study, we characterized the DNA-binding and transactivation properties of mouse Pax4. Repetitive rounds of PCR-based selection led to identification of the optimal DNA-binding sequences for the PD of Pax4. In agreement with the conservation of the optimal binding sequences among the Pax family transcription factors, Pax4 could bind to the potential binding sites for Pax6, another member of the Pax family also involved in endocrine pancreas development. The overexpression of Pax4 in HIT-T15 cells dose dependently inhibited the basal transcriptional activity as well as Pax6-induced activity. Detailed domain mapping analyses using GAL4-Pax4 chimeras revealed that the C-terminal region of Pax4 contains both activation and repression domains. The activation domain was active in the embryonic kidney-derived 293/293T cells and embryonal carcinoma-derived F9 cells, containing adenoviral E1A protein or E1A-like activity, respectively but was inactive or very weakly active in other cells including those of pancreatic beta - and alpha -cell origin. Indeed, the exogenous overexpression of type 13S E1A in heterologous cell types could convert the activation domain to an active one. On the other hand, the repression domain was active regardless of the cell type. When the repression domain was linked to the transactivation domain of a heterologous transcription factor, PDX-1, it could completely abolish the transactivation potential of PDX-1. These observations suggest a primary role of Pax4 as a transcriptional repressor whose function may involve the competitive inhibition of Pax6 function. The identification of the E1A-responsive transactivation domain, however, indicates that the function of Pax4 is subject to posttranslational regulation, providing further support for the complexity of mechanisms that regulate pancreas development.

* Corresponding author. Mailing address: Department of Internal Medicine and Therapeutics, A8, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka Pref. 565-0871, Japan. Phone: (81-6) 6879-3633. Fax: (81-6) 6879-3639. E-mail: kajimoto{at}medone.med.osaka-u.ac.jp.

Molecular and Cellular Biology, December 1999, p. 8281-8291, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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