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Heterodimerization with Fra-1 cooperates with the ERK pathway to stabilize c-Jun in response to the RAS oncoprotein

Oncogene volume 29, pages 4732–4740 (2010)Cite this article

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Abstract

Multiple tumorigenic pathways converge on the activating protein-1 (AP-1) family of dimeric transcription complexes by affecting transcription, mRNA decay, posttranslational modifications, as well as stability of its JUN and FOS components. Several mechanisms have been implicated in the phosphorylation- and ubiquitylation-dependent control of c-Jun protein stability. Although its dimer composition has a major role in the regulation of AP-1, little is known about the influence of heterodimerization partners on the half-life of c-Jun. The FOS family member Fra-1 is overexpressed in various tumors and cancer cell lines wherein it controls motility, invasiveness, cell survival and cell division. Oncogene-induced accumulation of Fra-1 results from both increased transcription and phosphorylation-dependent stabilization of the protein. In this report, we describe a novel role of Fra-1 as a posttranslational regulator of c-Jun. By using both constitutively and inducible transformed rat thyroid cell lines, we found that c-Jun is stabilized in response to RAS oncoprotein expression. This stabilization requires the activity of the extracellular signal-related kinase (ERK) pathway, along with c-Jun heterodimerization with Fra-1. In particular, heterodimerization with Fra-1 inhibits c-Jun breakdown by a mechanism dependent on the phosphorylation of the Fra-1 C-terminal domain that positively controls the stability of the protein in response to ERK signaling. Therefore, Fra-1 modulates AP-1 dimer composition by promoting the accumulation of c-Jun in response to oncogenic RAS signaling.

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Acknowledgements

We thank Roberto Di Lauro for the FRTL-5ER-RAS cell line, and Dirk Bohmann, Claus Nerlov and Latifa Bakiri for expression vectors encoding various c-Jun derivatives. We also thank Ingram Iaccarino for critical reading of this paper. This work was supported by grants to Pasquale Verde from AIRC (Associazione Italiana per la Ricerca sul Cancro), AICR (Association for International Cancer Research, UK) and PRIN-MIUR (Ministero dell′Istruzione, Università e Ricerca). Marc Piechaczyk's group is an ‘Equipe Labellisée’ of the French ‘Ligue Nationale contre le Cancer’. Jihane Basbous was supported by an INCA contract. Exchanges between the two laboratories received support of the PAI ‘Galileo’.

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Author notes

  1. T Mega

    Present address: 3Current address: Department of Experimental and Clinical Medicine, University of Catanzaro Magna Graecia, Catanzaro, Italy.,

  2. J Basbous

    Present address: 4Current address: Institut de Génétique Humaine, Montpellier, France.,

Authors and Affiliations

  1. Institute of Genetics and Biophysics ‘A. Buzzati Traverso,’ CNR, Naples, Italy

    F Talotta, T Mega, L Casalino & P Verde

  2. Institut de Génétique Moléculaire de Montpellier, CNRS, Universités Montpellier I et II, UMR 5535, Montpellier, France

    G Bossis, J Basbous, I Jariel-Encontre & M Piechaczyk

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  1. F Talotta
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Correspondence to P Verde.

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Talotta, F., Mega, T., Bossis, G. et al. Heterodimerization with Fra-1 cooperates with the ERK pathway to stabilize c-Jun in response to the RAS oncoprotein. Oncogene 29, 4732–4740 (2010). https://doi.org/10.1038/onc.2010.211

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