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

F. Talotta , T. Mega , G. Bossis (1) , L. Casalino , J. Basbous (1, 2) , I. Jariel-Encontre (1) , Marc Piechaczyk (1) , P. Verde

1 IGMM - Institut de Génétique Moléculaire de Montpellier
2 IGH - Institut de génétique humaine

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.

Mots clés: Animals Cell Line; Transformed Dimerization Extracellular Signal-Regulated MAP Kinases/*metabolism *MAP Kinase Signaling System Phosphorylation Proto-Oncogene Proteins c-fos/biosynthesis/genetics/*metabolism Proto-Oncogene Proteins c-jun/biosynthesis/genetics/*metabolism Rats Thyroid Gland/enzymology/metabolism Transcription Factor AP-1/metabolism Up-Regulation ras Proteins/biosynthesis/genetics

Domaines: Biochimie, Biologie Moléculaire

F. Talotta, T. Mega, G. Bossis, L. Casalino, J. Basbous, et al.. Heterodimerization with Fra-1 cooperates with the ERK pathway to stabilize c-Jun in response to the RAS oncoprotein. Oncogene, 2010, 29 (33), pp.4732--40. ⟨10.1038/onc.2010.211⟩. ⟨hal-02193625⟩