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Molecular and Cellular Biology, April 2002, p. 2575-2585, Vol. 22, No. 8
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.8.2575-2585.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Autoinhibitory Regulation of p73 by {Delta}Np73 To Modulate Cell Survival and Death through a p73-Specific Target Element within the {Delta}Np73 Promoter

Takahito Nakagawa,1,2 Masato Takahashi,1,2 Toshinori Ozaki,1 Ken-ichi Watanabe,1,2 Satoru Todo,2 Hiroyuki Mizuguchi,3 Takao Hayakawa,3 and Akira Nakagawara1*

Division of Biochemistry, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba 260-8717,1 Department of General Surgery, Hokkaido University School of Medicine, Kita-ku, Sapporo 060-8638,2 Division of Biological Chemistry and Biologicals, National Institute of Health Science, Setagaya-ku, Tokyo 158-8501, Japan3

Received 13 August 2001/ Returned for modification 9 October 2001/ Accepted 7 January 2002

p73 is a p53-related tumor suppressor but is also induced by oncogene products such as E2F-1, raising a question as to whether p73 is a tumor suppressor gene or oncogene. Unlike p53, p73 has several variants, including {Delta}Np73, which lacks the NH2-terminal transactivation domain. Although, in developing neurons, {Delta}Np73 is expressed abundantly and seems to inhibit the proapoptotic function of p53, the role of p73 and {Delta}Np73 and their regulatory mechanism in cell growth and differentiation are poorly understood. Here we report that p73, but not p53, directly activates the transcription of endogenous {Delta}Np73 by binding to the p73-specific target element located at positions -76 to -57 within the {Delta}Np73 promoter region. The activation of {Delta}Np73 promoter by p63 was marginal. {Delta}Np73 was associated with p73{alpha}, p73ß, and p53, as demonstrated by immunoprecipitation assays, and inhibited their transactivation activities when we used reporters of Mdm2, Bax, or {Delta}Np73 itself in SAOS-2 cells. Furthermore, induction or overexpression of {Delta}Np73 promoted cell survival by competing with p53 and p73 itself. Thus, our results suggest that the negative feedback regulation of p73 by its target {Delta}Np73 is a novel autoregulatory system for modulating cell survival and death.

* Corresponding author. Mailing address: Division of Biochemistry, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan. Phone: 81-43-264-5431. Fax: 81-43-265-4459. E-mail: akiranak{at}chiba-ccri.chuo.chiba.jp.

Molecular and Cellular Biology, April 2002, p. 2575-2585, Vol. 22, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.8.2575-2585.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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