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

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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 transactivationproperties of mouse Pax4. Repetitive rounds of PCR-based selectionled to identification of the optimal DNA-binding sequences forthe PD of Pax4. In agreement with the conservation of the optimalbinding sequences among the Pax family transcription factors,Pax4 could bind to the potential binding sites for Pax6, anothermember of the Pax family also involved in endocrine pancreas development.The overexpression of Pax4 in HIT-T15 cells dose dependently inhibitedthe basal transcriptional activity as well as Pax6-induced activity.Detailed domain mapping analyses using GAL4-Pax4 chimeras revealedthat the C-terminal region of Pax4 contains both activation andrepression domains. The activation domain was active in the embryonickidney-derived 293/293T cells and embryonal carcinoma-derivedF9 cells, containing adenoviral E1A protein or E1A-like activity,respectively but was inactive or very weakly active in other cellsincluding those of pancreatic $beta$ - and $alpha$ -cell origin. Indeed, theexogenous overexpression of type 13S E1A in heterologous celltypes could convert the activation domain to an active one. Onthe other hand, the repression domain was active regardless ofthe cell type. When the repression domain was linked to the transactivationdomain of a heterologous transcription factor, PDX-1, it couldcompletely abolish the transactivation potential of PDX-1. Theseobservations suggest a primary role of Pax4 as a transcriptionalrepressor whose function may involve the competitive inhibitionof Pax6 function. The identification of the E1A-responsive transactivationdomain, however, indicates that the function of Pax4 is subjectto posttranslational regulation, providing further support forthe complexity of mechanisms that regulate pancreasdevelopment.

^* Corresponding author. Mailing address: Department of Internal Medicine and Therapeutics, A8, Osaka University Graduate Schoolof 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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