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The structural determinants responsible for c-Fos protein proteasomal degradation differ according to the conditions of expression

Oncogene volume 22, pages 1461–1474 (2003)Cite this article

Abstract

c-fos gene is expressed constitutively in a number of tissues as well as in certain tumor cells and is inducible, in general rapidly and transiently, in virtually all other cell types by a variety of stimuli. Its protein product, c-Fos, is a short-lived transcription factor that heterodimerizes with various protein partners within the AP-1 transcription complex via leucine zipper/leucine zipper interactions for binding to specific DNA sequences. It is mostly, if not exclusively, degraded by the proteasome. To localize the determinant(s) responsible for its instability, we have conducted a genetic analysis in which the half-lives of c-Fos mutants and chimeras made with the stable EGFP reporter protein were compared under two experimental conditions taken as example of continous and inducible expression. Those were constitutive expression in asynchronously growing Balb/C 3T3 mouse embryo fibroblasts and transient induction in the same cells undergoing the G0/G1 phase transition upon stimulation by serum. Our work shows that c-Fos is degraded faster in synchronous- than in asynchronous cells. This difference in turnover is primarily accounted for by several mechanisms. First, in asynchronous cells, a unique C-terminal destabilizer is active whereas, in serum-stimulated cells two destabilizers located at both extremities of the protein are functional. Second, heterodimerization and/or binding to DNA accelerates protein degradation only during the G0/G1 phase transition. Adding another level of complexity to turnover control, phosphorylation at serines 362 and 374, which are c-Fos phosphorylation sites largely modified during the G0/G1 phase transition, stabilizes c-Fos much more efficiently in asynchronous than in serum-stimulated cells. In both cases, the reduced degradation rate is due to inhibition of the activity of the C-terminal destabilizer. However, in serum-stimulated cells, this effect is partially masked by the activation of the N-terminal destabilizer and basic domain/leucine zipper-dependent mechanisms. Taken together, our data show that multiple degradation mechanisms, differing according to the conditions of expression, may operate on c-Fos to ensure a proper level and/or timing of expression. Moreover, they also indicate that the half-life of c-Fos during the G0/G1 phase transition is determined by a delicate balance between opposing stabilizing and destabilizing mechanisms operating at the same time.

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Abbreviations

DBD:

DNA-binding domain

LZ:

leucine zipper

bZIP:

basic DNA-binding domain/leucine zipper

EGFP:

Enhanced green fluorescent protein

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Acknowledgements

This work was supported by grants from the CNRS, the Association de Recherche contre le Cancer and the Quality of Life Program of the European Community (contract QLG1-CT-2001-02026). PF is a recipient of the Ligue contre le Cancer. We are grafetul to Dr O Coux for stimulating discussions and to Dr P Travo for helpful advices concerning fluorescence miscroscope analysis.

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  1. Claire Acquaviva

    Present address: Wellcome/CRC Institute, Tennis Court Road, CB2 1QR, UK

Authors and Affiliations

  1. Insitut de Génétique Moléculaire, UMR 5535/IFR24, CNRS, 1919, Route de Mende, Montpellier, Cédex 05, 34293, France

    Patrizia Ferrara, Elisabetta Andermarcher, Guillaume Bossis, Claire Acquaviva, Frédérique Brockly, Isabelle Jariel-Encontre & Marc Piechaczyk

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Ferrara, P., Andermarcher, E., Bossis, G. et al. The structural determinants responsible for c-Fos protein proteasomal degradation differ according to the conditions of expression. Oncogene 22, 1461–1474 (2003). https://doi.org/10.1038/sj.onc.1206266

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