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AP-1 factors play an important role in transformation induced by the v-rel oncogene
J Kralova1, A S Liss, W Bargmann
1Department of Microbiology and the Institute for Cellular and Molecular Biology, University of Texas at Austin, 78712-1095, USA.
Abstract:
v-rel is the oncogenic member of the Rel/NF-kappaB family of transcription factors. The mechanism by which v-Rel induces transformation of avian lymphoid cells and fibroblasts is not precisely known. However, most models propose that v-rel disrupts the normal transcriptional regulatory network. In this study we evaluated the role of AP-1 family members in v-Rel-mediated transformation. The overexpression of v-Rel, c-Rel, and c-Rel delta resulted in a prolonged elevation of c-fos and c-jun expression and in a sustained repression of fra-2 at both the mRNA and protein levels in fibroblasts and lymphoid cells. Moreover, the transforming abilities of these Rel proteins correlated with their ability to alter the expression of these AP-1 factors. v-Rel exhibited the most pronounced effect, whereas c-Rel, with poor transforming ability, elicited only moderate changes in AP-1 levels. Furthermore, c-Rel delta, which exhibits enhanced transforming potential relative to c-Rel, induced intermediate changes in AP-1 expression. To directly evaluate the role of AP-1 family members in the v-Rel transformation process, a supjun-1 transdominant mutant was used. The supjun-1 mutant functions as a general inhibitor of AP-1 activity by inhibiting AP-1-mediated transactivation and by reducing AP-1 DNA-binding activity. Coinfection or sequential infection of fibroblasts or lymphoid cells with viruses carrying rel oncogenes and supjun-1 resulted in a reduction of the transformation efficiency of the Rel proteins. The expression of supjun-1 inhibited the ability of v-Rel transformed lymphoid cells and fibroblasts to form colonies in soft agar by over 70%. Furthermore, the expression of supjun-1 strongly interfered with the ability of v-Rel to morphologically transform avian fibroblasts. This is the first report showing that v-Rel might execute its oncogenic potential through modulating the activity of early response genes.
Insights
The oncogenic protein v-Rel transforms cells by altering the expression of AP-1 family members, including c-Fos and c-Jun. Inhibiting AP-1 activity with supjun-1 significantly reduces v-Rel
Area of Science:
- Molecular Biology
- Oncology
- Cellular Transformation
Background:
- v-Rel is an oncogenic transcription factor from the Rel/NF-kappaB family implicated in avian cell transformation.
- The precise mechanism of v-Rel-induced transformation, particularly its effect on transcriptional networks, remains unclear.
- AP-1 family members (e.g., c-Fos, c-Jun, Fra-2) are key regulators of cellular processes, including proliferation and differentiation.
Purpose of the Study:
- To investigate the role of AP-1 family members in v-Rel-mediated transformation of avian lymphoid cells and fibroblasts.
- To determine if alterations in AP-1 expression correlate with the transforming potential of v-Rel and related proteins (c-Rel, c-Rel delta).
Main Methods:
- Overexpression of v-Rel, c-Rel, and c-Rel delta in avian cells to assess changes in c-fos, c-jun, and fra-2 mRNA and protein levels.
- Correlation analysis between the transforming abilities of Rel proteins and their impact on AP-1 factor expression.
- Utilized a transdominant mutant supjun-1 to inhibit AP-1 activity and evaluated its effect on v-Rel-mediated cell transformation and colony formation.
Main Results:
- Overexpression of v-Rel, c-Rel, and c-Rel delta led to sustained elevation of c-fos and c-jun, and repression of fra-2.
- The transforming potential of Rel proteins correlated with their ability to modulate AP-1 expression levels, with v-Rel showing the most pronounced effect.
- Inhibition of AP-1 activity by supjun-1 significantly reduced the transformation efficiency of v-Rel, decreasing soft agar colony formation by over 70% and interfering with morphological transformation.
Conclusions:
- v-Rel oncogenic activity is mediated, at least in part, through the modulation of AP-1 family member expression and activity.
- This study provides the first evidence linking v-Rel's oncogenic potential to the dysregulation of early response genes like AP-1 factors.
- Targeting AP-1 activity represents a potential strategy to counteract v-Rel-induced cellular transformation.