Transient expression of E1A and Ras oncogenes causes downregulation of c-fos gene transcription in nontransformed REF52 cells

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 þ 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 þ 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.

ERK-associated changes of AP-1 proteins during fear extinction

“…The question why this phenomenon is only observed after extinction needs further investigation. Our hypothesis that ERK may form complexes with HDAC1 or mSin3A, which are known to repress c-Fos (Usenko et al, 2003; Yang et al, 2001) was not confirmed. The possibility remains that pERK targets JunD and JDP2 to AP-1 and subsequently dephosphorylates and dissociates from them.…”

HDAC1 Regulates Fear Extinction in Mice

“…HDAC1 activity has been implicated in the regulation of the expression of c-Fos (Yang et al, 2001;Usenko et al, 2003;Renthal et al, 2008), an immediate early gene that is transiently upregulated after contextual fear conditioning (Radulovic et al, 1998;Peleg et al, 2010) and whose protein levels are reduced after extinction training (Tronson et F ϭ 12,78). B, Top, Experimental design.…”

Identification of genes differentially expressed as result of adenovirus type 5- and adenovirus type 12-transformation

“…Many of the pathways in the merged networks shown in Figure 7c converge on FOS, one of the downstream effectors of the MAPK/Erk signalling cascade involved in growth and differentiation, which the comparative analysis suggests is significantly dysregulated in the Ad5 E1-TC (Figure 4 ). Expression of c-fos is suppressed in some human tumours [ 27 ] and also in rat embryo fibroblast cells transiently transfected or stably transformed by Ad E1A and Ras, acting on chromatin remodelling factors [ 28 ]. The extracellular signal-regulated kinase (ERK) pathway is one of three major mammalian mitogen-activated protein kinase (MAPK) signalling pathways; the others being the p38 MAPK pathway, and the c-Jun NH 2 -terminal kinase (JNK) pathway.…”