Related Experiment Videos
Distinct roles of Jun : Fos and Jun : ATF dimers in oncogenesis
1Department of Molecular Cell Biology, Leiden University Medical Center, Sylvius Laboratories, PO Box 9503, 2300 RA Leiden, The Netherlands.
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.
Insights
Jun:Fos and Jun:ATF dimers have distinct roles in oncogenesis. Jun:ATF2 dimers, not Jun:Fra2, trigger fibrosarcomas by repressing SPARC, highlighting their roles in cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Signaling
Background:
- Activating Protein-1 (AP-1) dimers, including Jun:Fos and Jun:ATF complexes, bind distinct AP-1 sites.
- These dimers are differentially regulated by cellular signaling and oncogenes, suggesting varied functional roles.
Purpose of the Study:
- To differentiate the functions of Jun:Fos, Jun:ATF, and Jun:Jun dimers in oncogenesis.
- To investigate the specific roles of Jun dimerization mutants in cellular transformation and tumor development.
Main Methods:
- Development of Jun dimerization mutants to restrict specific dimerization partners (Jun:Jun, Jun:Fos, Jun:ATF).
- Introduction of these mutants into chicken embryo fibroblasts to assess in vitro oncogenesis.
- Analysis of tumor development in chicken wings and identification of target genes.
Main Results:
- Jun:Fra2 and Jun:ATF2 dimers induce anchorage independence and growth factor independence, respectively.
- v-Jun:ATF2, not v-Jun:Fra2, triggers primary fibrosarcoma development in chicken wings.
- Extracellular matrix genes, including SPARC, are key targets of v-Jun:ATF2; SPARC repression is crucial for fibrosarcoma induction.
Conclusions:
- Jun:Fos and Jun:ATF dimers play distinct, complementary roles in oncogenesis.
- Jun:ATF2 dimers are critical for fibrosarcoma development, partly through repression of SPARC.
- Avian cell systems with Jun dimerization mutants are valuable tools for studying oncogenesis pathways.