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Distinct roles of Jun : Fos and Jun : ATF dimers in oncogenesis

Abstract

Jun : Fos and Jun : ATF complexes represent two classes of AP-1 dimers that (1) preferentially bind to either heptameric or octameric AP-1 binding sites, and (2) are differently regulated by cellular signaling pathways and oncogene products. To discriminate between the functions of Jun : Fos, Jun : ATF and Jun : Jun, mutants were developed that restrict the ability of Jun to dimerize either to itself, or to Fos(-like) or ATF(-like) partners. Introduction of these mutants in chicken embryo fibroblasts shows that Jun : Fra2 and Jun : ATF2 dimers play distinct, complementary roles in in vitro oncogenesis by inducing either anchorage independence or growth factor independence, respectively. v-Jun : ATF2 rather than v-Jun : Fra2 triggers the development of primary fibrosarcomas in the chicken wing. Genes encoding extracellular matrix components seem to constitute an important subset of v-Jun : ATF2-target genes. Repression of the matrix component SPARC by Jun is essential for the induction of fibrosarcomas. Avian primary cells transformed by either Jun : Fra2 or Jun : ATF2 thus provide powerful tools for the investigation of the downstream pathways involved in oncogenesis. Further genetic studies with Jun dimerization mutants will be required to be precise and extend the specific roles of the Jun : Fos and Jun : ATF dimers during cancer progression in avian and mammalian systems.

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Acknowledgements

H van Dam was supported by grants from the Royal Netherlands Academy of Arts and Sciences (KNAW), the EU Training and Mobility of Researchers Program (TMR CT96-0044), the Dutch Cancer Society (RUL 97/1405), the European Economic Community Biomedicine and Health Program (Biomed II BMH4 CT98-3505) and the Netherlands Organization for Scientific Research (NWO 901-02-221). M Castellazzi was supported by grants from the Association pour la Recherche sur le Cancer, from the Mutuelle Générale de l'Education Nationale, and from the European Economic Community Biomedicine and Health Program (Biomed II contract n° BMH4 CT98-3505).

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van Dam, H., Castellazzi, M. Distinct roles of Jun : Fos and Jun : ATF dimers in oncogenesis. Oncogene 20, 2453–2464 (2001). https://doi.org/10.1038/sj.onc.1204239

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