The E2F transcription factor family and survivin play a crucial role in maintaining homeostasis by coupling the vital processes of cell division and apoptosis. Deregulation of E2F or survivin signaling, lead to developmental defects in mice and are hallmarks of virtually every human cancer.
Functionally, the mammalian E2F family consists of activators (E2F1-2 and E2F3a) and repressors (E2F3b and E2F4-8), which regulate cellular proliferation, apoptosis and differentiation. E2F7 and E2F8, which are the last two discovered mouse E2F family members, structurally form a sub-class within the repressor E2Fs. E2F7-8 are distinct in having a duplicated DNA binding domain, which is highly conserved across all the E2F family members. Both E2F7 and E2F8 inhibit cellular proliferation when overexpressed in mouse embryonic fibroblasts (MEFs). Expression of E2F7 and E2F8 are cell cycle regulated and are detected in the same adult mouse tissues suggesting a functional overlap or synergy.
Consistent with the expanding complexity and functional diversity of the large mammalian E2F family, a cell cycle checkpoint is also regulated by the E2Fs. Simultaneous deletion of E2F1, E2F2 and E2F3, leads to a severe proliferative defect in the MEFs, correlating with the upregulation of p21 and the absence of cyclin dependent kinase activity.
A proliferative defect is also observed in the MEFs conditionally deleted for survivin, a direct transcriptional target of the E2Fs. Survivin performs dual functions as a regulator of cell division and as an anti-apoptotic protein. During cell division, survivin ensures high fidelity chromosomal segregation and proper cytokinesis. Accordingly, survivin deleted MEFs fail to proliferate and become increasingly polyploid with an abnormal nuclear morphology. However, they do not undergo apoptosis, indicating a role of survivin in proliferation but not survival. Additionally, MEFs transformed with oncogenes c-Myc and H-RasV12 fail to proliferate following conditional deletion of survivin, demonstrating a requirement for survivin in the maintenance of transformation. Preliminary evidence also suggests that survivin is capable of collaborating with c-Myc or H-RasV12 in transforming MEFs, unraveling a novel role for survivin in cancer initiation.
Collectively, these data uncover important roles of the E2F family and survivin in cellular proliferation and transformation.
|School:||The Ohio State University|
|School Location:||United States -- Ohio|
|Source:||DAI-B 79/09(E), Dissertation Abstracts International|
|Keywords:||Cellular, E2f, Players, Proliferation, Survivin|
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