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Journal of Virology, November 1998, p. 8510-8516, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Inactivation of p53 but Not p73 by Adenovirus Type 5 E1B 55-Kilodalton and E4 34-Kilodalton Oncoproteins

Judith Roth,1 Claudia König,2 Sandra Wienzek,2 Silke Weigel,2 Susanne Ristea,2 and Matthias Dobbelstein2,*

Zentrum für Innere Medizin, Abteilung Gastroenterologie und Stoffwechsel, Fachbereich Medizin der Philipps-Universität Marburg, 35043 Marburg,1 and Institut für Virologie, Zentrum für Mikrobiologie und Hygiene, Philipps-Universität Marburg, 35037 Marburg,2 Germany

Received 9 June 1998/Accepted 31 July 1998

The adenovirus E1B 55-kDa and E4 34-kDa oncoproteins bind and inactivate the p53 tumor suppressor gene product, resulting in cell transformation. A recently discovered cellular protein, p73, shows extensive similarities to p53 in structure and function. Here we show that the simultaneous transient expression of E1B 55-kDa and E4 34-kDa proteins is sufficient to drastically shorten the intracellular half-life of p53, leading to strongly reduced steady-state p53 levels. Concomitantly, the E1B 55-kDa and E4 34-kDa proteins act synergistically to inactivate the transcriptional activity of p53. Mutational analysis suggests that physical interactions between the E1B 55-kDa protein and p53 and between the E1B 55-kDa and E4 34-kDa proteins are both required for p53 degradation. In contrast, the ability of p53 to interact with the cellular mdm2 oncoprotein or with its cognate DNA element appears to be dispensable for its destabilization by adenovirus gene products. The adenovirus E1B 55-kDa protein did not detectably interact with p73 and failed to inhibit p73-mediated transcription; also, the E1B 55-kDa and E4 34-kDa proteins did not promote p73 degradation. When five amino acids near the amino termini were exchanged at corresponding positions between p53 and p73, this rendered p53 resistant and p73 susceptible to complex formation and inactivation by the E1B 55-kDa protein. Our results suggest that while p53 inactivation is a central step in virus-induced tumor development, efficient transformation can occur without targeting p73.

* Corresponding author. Mailing address: Institut für Virologie, Zentrum für Mikrobiologie und Hygiene, Philipps-Universität Marburg, Robert Koch Str. 17, 35037 Marburg, Germany. Phone: 49 6421 28 3302. Fax: 49 6421 28 8962. E-mail: dobbelst{at}mailer.uni-marburg.de.

Journal of Virology, November 1998, p. 8510-8516, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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