Fos family members: regulation, structure and role in oncogenic transformation

The members of the Fos protein family might be subdivided in two groups, ac cording to their ability to transform rodent fibroblasts, transforming (c-F os and FosB) and non-transforming (Fra-1 and Fra-2) proteins. Members of th ese groups are differently activated in response to external stimuli and po sses different structural features. Importantly, whilst c-Fos and FosB cont ain multiple transactivation modules in their N- and C-terminal parts, tran sactivation domains are absent in the non-transforming Fos proteins. As a r esult, Fra-1 and Fra-2 though efficiently form dimers with the Jun proteins , are weak transcriptional activators and inhibit the c-Fos-dependent activ ation in transient transfection assay. The numerous experiments performed w ith the different Fos mutant proteins with impaired transforming ability, a s well as with chimeric proteins revealed the importance of the transactiva tion function for transformation. Fra-1 and Fra-2 proteins albeit ineffecti vely triggering oncogenic transformation, are abundant in ras- and src-tran sformed murine and chicken fibroblasts, in neoplastic thyroid cells and in highly malignant mouse adenocarcinoma cells, which underwent mesenchymal tr ansition. The abundance of the non-transforming Fos proteins in these syste ms might be mediated by a positive AP-1-dependent feedback mechanism, as we ll as by wnt signals. Furthermore, the manipulation of the Fra-1 expression level in thyroid and mammary tumor cells modulated the transcription of se veral tumor progression markers and affected cell morphology and invasivene ss. These recent data demonstrate a novel function of non-transforming Fos proteins in the maintenance and progression of the transformed state. Inter estingly, this function is independent of the documented invalidity of the Fra-1 and Fra-2 proteins as transcriptional activators in rodent fibroblast s.