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Molecular and Cellular Biology, May 1999, p. 3289-3298, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Ubiquitination and Degradation of ATF2 Are Dimerization Dependent

Serge Y. Fuchs and Ze'ev Ronai*

The Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029

Received 22 September 1998/Returned for modification 4 November 1998/Accepted 25 January 1999

Ubiquitination and proteasome-dependent degradation are key determinants of the half-lives of many transcription factors. Homo- or heterodimerization of basic region-leucine zipper (bZIP) transcription factors is required for their transcriptional activities. Here we show that activating transcription factor 2 (ATF2) heterodimerization with specific bZIP proteins is an important determinant of the ubiquitination and proteasome-dependent degradation of ATF2. Depletion of c-Jun as one of the ATF2 heterodimer partners from the targeting proteins decreased the efficiency of ATF2 ubiquitination in vitro, whereas the addition of exogenously purified c-Jun restored it. Similarly, overexpression of c-Jun in 293T human embryo kidney cells increased ATF2 ubiquitination in vivo and reduced its half-life in a dose-dependent manner. Mutations of ATF2 that disrupt its dimerization inhibited ATF2 ubiquitination in vitro and in vivo. Conversely, removal of residues 150 to 248, as in a constitutively active ATF2 spliced form, enhanced ATF2 dimerization and transactivation, which coincided with increased ubiquitination and decreased stability. Our findings indicate the increased sensitivity of transcriptionally active dimers of ATF2 to ubiquitination and proteasome-dependent degradation. Based on these observations, we conclude that increased targeting of a transcriptionally active ATF2 form indicates the mechanism by which the magnitude and the duration of the cellular stress response are regulated.

* Corresponding author. Mailing address: The Ruttenberg Cancer Center, Mount Sinai School of Medicine, One Gustave L. Levy Pl., Box 1130, New York, NY 10029. Phone: (212) 824-8193. Fax: (212) 849-2446. E-mail: ronaiz01{at}doc.mssm.edu.

Molecular and Cellular Biology, May 1999, p. 3289-3298, Vol. 19, No. 5
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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