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Links to deliverables and publications from FP7 projects, as well as links to some specific result types such as dataset and software, are dynamically retrieved from OpenAIRE .
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A model of rat embryo fibroblasts (REF) cells immortalized by Ad5-E1A oncogene and transformed by AdS-EIA+Ha-Ras oncogenes was utilized to study the changes in DNA-binding activity and the composition of transcription factors controlling cell proliferation and differentiation. It has been demonstrated that E1A+Ha-Ras cells are characterized by high and constitutive levels of DNA-binding activity of transcription factors regulated through Ras-dependent (AP-1) and Ras-independent (Stat 1) signal transduction pathways. Moreover, we showed that AP-1 complexes were greatly changed in composition from those containing Fos/Jun heterodimers to Fra-l/Jun and Jun/ATF-2, Jun/ATFa heterodimers.
Transcription factor Stat 1, which revealed constitutive DNA-binding activity and nuclear localization in EIA+Ha-Ras cells, was found to be permanently phosphorylated at an unique tyrosine residue, probably due to the constitutive activity of epidermal growth factor receptor on the cell membrane. Moreover, immunoprecipitation with Stat 1-antibodies revealed its association with MAM kinases (42 and 44 kD). Therefore, it can be additionally phosphorylated by the MAP kinases for full activity. These data are interpreted as a possible cross-talk between Ras- and Stat-pathways.
A study of the function of p53/Rb tumor-suppressor pathway demonstrated that this pathway is functioning in response to DNA damage at p53/Waf1 protein levels. But Waf1 as a universal inhibitor of cyclin-dependent kinases is defective downstream at least on a level of inhibiting the activity of cyclin-associated kinases. Inactivation of Waf1 inhibitory activity is supposed to be provided by its interaction with ElA oncoproducts. DNA damage induced by -irradiation of EIA+Ha-Ras transformed cell, which have a combination of active wil-type p53 and functionally inactive Waf1 inhibitor, promotes G2/M arrest followed by polyploidy and death of the polyploid cells due to apoptosis.
Thus, deregulation of different signal transduction pathways shown in this work is an indispensable step of cell transformation by the oncogenes we have used and this deregulation leads to autonomous proliferation of E1A+Ha-Ras cells in the absence of growth factors and to apoptotic death after DNA damage.
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