Transactivation of gene expression by nuclear and cytoplasmic rel proteins.

Abstract

Transcriptional activation of gene expression by oncogenic proteins can lead to cellular transformation. It has recently been demonstrated that the protein encoded by the v-rel oncogene from reticuloendotheliosis virus strain T can transactivate gene expression from certain promoters in a cell-specific manner. We have examined the cytological location, transforming properties, and transactivation properties of proteins encoded by chimeric turkey v-rel/chicken c-rel genes. We found that whereas the v-rel protein was nuclear in both chicken embryo and rat fibroblasts, the presence of the C terminus of the c-rel protein inhibited nuclear localization of the rel protein in these fibroblasts. Cytoplasmic rel proteins containing C-terminal c-rel sequences transactivated gene expression from the polyomavirus late promoter as efficiently as did similar rel proteins located in the nucleus. These results indicate that the cellular location of rel proteins is not important for transactivation of gene expression and suggest that transactivation by rel proteins is indirect, perhaps by affecting an intracellular signal transduction pathway that eventually results in the alteration of gene expression. The transforming properties of the rel protein were unaltered by the presence of the c-rel C terminus, but, as previously reported for turkey c-rel sequences, substitution of chicken c-rel sequences for internal v-rel sequences reduced the transforming activity of the rel protein and eliminated the immortalization ability. However, all of the chimeric v/c-rel proteins were able to transactivate gene expression, indicating that transactivation does not correlate with transformation. These results suggest that transactivation may be necessary but is not sufficient for transformation by rel proteins.Recent evidence demonstrates that alteration of gene expression by oncogenic proteins can lead to cellular transformation. There are several mechanisms by which oncogenic proteins can alter gene expression. Certain oncogenes are thought to encode proteins that function as direct transactivators of transcription (23). A prototype of this group of oncogenic proteins is the v-jun oncogene. The v-and c-jun proteins are located in the nucleus, bind to DNA in a sequence-specific manner, and interact with other cellular proteins involved in transcription (3, 4). Both the oncogenic and the cellular proto-oncogenic jun proteins are able to activate transcription (3, 4), and cellular transformation by these oncogenic proteins probably results from subtle differences between the activation of genes by the oncogenic proteins and by the proto-oncogenic proteins. Alterations in gene expression have also been shown to result from expression of oncogenic proteins that are not directly involved in transcription. Autocrine expression of the v-sis oncogene results in the activation of transcription of many genes, including c-fos and c-myc (1,15,16,25,27). The v-mos oncogene has been shown to alter expression from the alpha-2 collagen promoter (32), and bot...

An optimal range of transcription potency is necessary for efficient cell transformation by c-Rel to ensure optimal nuclear localization and gene-specific activation

“…Together with our analysis of c-Rel mutants, these data underscore the important role of cTAD2 in the subcellular localization of Rel proteins and indicate that particular mutations in the Rel TADs can affect gene-specific expression and be a determining factor for cell transformation. Our findings agree with reports suggesting a role for c-Rel's C-terminus in its cytoplasmic anchoring and negative regulation by IkBa (Figure 4; Hannink and Temin, 1989;Capobianco et al, 1990;Diehl et al, 1993;Starczynowski et al, 2003;Iwai et al, 2005). cTAD2 mutations that dampen negative feedback by IkBa are likely to enable long-lasting activation of genes important for cell transformation, as seen for ch-IAP1 (Kralova et al, 2002).…”

Degradation of Proto-oncoprotein c-Rel by the Ubiquitin-Proteasome Pathway

“…In the C-terminal 80 amino acids, no arginine or lysine is found, and 30 out of 80 residues are PEST sequences. A similar observation was also made in avian c-Rel protein (35,48).…”

Conservation of transcriptional activation functions of the NF-kappa B p50 and p65 subunits in mammalian cells and Saccharomyces cerevisiae.

“…Similar transfection studies with p50 have failed to demonstrate transcriptional activation functions (7,57,60,64). Other studies have demonstrated that both c-rel and dorsal have activation domains within the C-terminal region (12,20,26,29,30,57). In contrast, by using an in vitro transcription assay, it has been shown that the rel homology domain of p50 is capable of transcriptional activation (19,39).…”