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Oncogenic capacity of the E2F1 gene
D G Johnson1, W D Cress, L Jakoi
1Department of Genetics, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710.
Abstract:
Previous experiments have identified the E2F transcription factor as a potential downstream target for the action of cellular regulatory activities, such as the Rb tumor suppressor protein, that control cell growth and that, when altered, contribute to the development of human tumors. In light of these findings, we have assayed the ability of the E2F1 and DP1 genes, which encode heterodimeric partners that together create E2F activity, to act in an oncogenic fashion. We find that E2F1, particularly in combination with the DP1 product, cooperates with an activated ras oncogene to induce the formation of morphologically transformed foci in primary rat embryo fibroblast cultures. In addition, an E2F1 chimeric protein, in which sequences involved in Rb binding have been replaced with the herpesvirus VP16 activation domain, exhibits increased transformation activity. Cells transfected with E2F1 and DP1 or the E2F1-VP16 chimera form colonies in soft agar and induce tumor formation in nude mice. We conclude that deregulated E2F1 expression and function can have oncogenic consequences.
Insights
The E2F1 transcription factor, especially with DP1, can promote cancer when its regulation is disrupted. This suggests E2F1
Area of Science:
- Molecular Biology
- Oncology
- Cellular Regulation
Background:
- The E2F transcription factor is a known target of cellular regulators like the Rb tumor suppressor protein.
- Alterations in cell growth control, involving E2F, are linked to human tumor development.
Purpose of the Study:
- To investigate the oncogenic potential of E2F1 and DP1 genes.
- To determine if E2F1 and DP1 can cooperate with oncogenes to drive cellular transformation.
Main Methods:
- Assayed E2F1 and DP1 gene function in cellular transformation.
- Utilized a chimeric E2F1 protein with an altered Rb-binding domain.
- Co-expressed genes with an activated ras oncogene in primary rat embryo fibroblast cultures.
- Assessed colony formation in soft agar and tumor formation in nude mice.
Main Results:
- E2F1, particularly with DP1, cooperates with activated ras to induce morphological transformation of fibroblasts.
- An E2F1-VP16 chimera showed enhanced transformation activity.
- Transfected cells formed colonies in soft agar and tumors in nude mice.
Conclusions:
- Disregulated E2F1 expression and function can lead to oncogenic consequences.
- E2F1 plays a significant role in cancer development, independent of Rb binding in some contexts.