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  • Title: Transient expression of E1A and Ras oncogenes causes downregulation of c-fos gene transcription in nontransformed REF52 cells.
    Author: Usenko T, Kukushkin A, Pospelova T, Pospelov V.
    Journal: Oncogene; 2003 Oct 23; 22(48):7661-6. PubMed ID: 14576829.
    Abstract:
    Stable transformation of rat embryo fibroblast (REF) cells with E1A and cHa-ras oncogenes leads to downmodulation of c-fos gene transcription. This repression is provided in part by the association of Elk-1 transcription factor with histone deacetylases mediated through effects of Ras on MAP-kinase cascades. Here, we focus on the primary effects of E1A and Ras displayed in transient transfection assay on the transactivating capability of Elk-1, which is a key transcription factor of c-fos gene regulation. Our data show that E1A is able to suppress serum- and Ras-induced stimulation of Gal-luc reporter activity by a full-length Gal-Elk1-428 fusion protein as well as the expression of c-fos promoter-driven luciferase constructs (fos-luc). The repression can be relieved by trichostatin A, a histone deacetylase (HDAC) inhibitor, implying the involvement of HDACs and an inactive chromatin structure formed due to underacetylation of nucleosomal histones. Thus, upon transient transfection of E1A and Ras oncogenes in REF52 cells or their stable expression in E1A+cHa-ras cells, E1A contributes to the formation of inactive chromatin structure through association with p300/CBP histone acetyltransferases at c-fos promoters, whereas Ras mediates its effect through constitutive activation of the MAP/ERK kinase cascade, thereby promoting the recruitment of HDAC1 to the Elk-1 transcription factor. As a result, downregulation of c-fos gene transcription revealed in established E1A+Ras transformants is unlikely to be a consequence of cell transformation itself, but follows from primary effects of E1A and Ras on chromatin remodeling factors.
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