Ubiquitination and degradation of ATF2 are dimerization dependent.
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.
Fuchs
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The Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029, USA.
Ronai
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D051698:Activating Transcription Factor 2; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors; D002154:Calpain / Q000378:metabolism; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D051790:G-Box Binding Factors; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D016350:Leucine Zippers / Q000235:genetics; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D009154:Mutation; D046988:Proteasome Endopeptidase Complex; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection; D014452:Ubiquitins / Q000378:metabolism*
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D051790:G-Box Binding Factors; D009097:Multienzyme Complexes; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D014452:Ubiquitins; D002154:Calpain; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex