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.
Heterodimerization with Fra-1 cooperates with the ERK pathway to stabilize c-Jun in response to the RAS oncoprotein
Talotta, F.; Mega, T.; Bossis, G.; Casalino, L.; Basbous, J.; Jariel-Encontre, I.; Piechaczyk, M.; Verde, P.
2010-08-19 / vol 29 / pages 4732-40
onc2010211 [pii] 10.1038/onc.2010.211
1476-5594 (Electronic) 0950-9232 (Linking)
Animals; Phosphorylation; Cell Line, Transformed; Rats; Up-Regulation; *MAP Kinase Signaling System; Dimerization; Extracellular Signal-Regulated MAP Kinases/*metabolism; Proto-Oncogene Proteins c-fos/biosynthesis/genetics/*metabolism; Proto-Oncogene Proteins c-jun/biosynthesis/genetics/*metabolism; ras Proteins/biosynthesis/genetics; Thyroid Gland/enzymology/metabolism; Transcription Factor AP-1/metabolism