Opavsky, R. et al. Specific tumor suppressor function for E2F2 in Myc-induced T cell lymphomagenesis. Proc. Natl Acad. Sci. USA 104, 15400-15405

Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine and Public Health, Ohio State University, Columbus, OH 43210, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2007; 104(39):15400-5. DOI: 10.1073/pnas.0706307104
Source: PubMed


Deregulation of the Myc pathway and deregulation of the Rb pathway are two of the most common abnormalities in human malignancies. Recent in vitro experiments suggest a complex cross-regulatory relationship between Myc and Rb that is mediated through the control of E2F. To evaluate the functional connection between Myc and E2Fs in vivo, we used a bitransgenic mouse model of Myc-induced T cell lymphomagenesis and analyzed tumor progression in mice deficient for E2f1, E2f2, or E2f3. Whereas the targeted inactivation of E2f1 or E2f3 had no significant effect on tumor progression, loss of E2f2 accelerated lymphomagenesis. Interestingly, loss of a single copy of E2f2 also accelerated tumorigenesis, albeit to a lesser extent, suggesting a haploinsufficient function for this locus. The combined ablation of E2f1 or E2f3, along with E2f2, did not further accelerate tumorigenesis. Myc-overexpressing T cells were more resistant to apoptosis in the absence of E2f2, and the reintroduction of E2F2 into these tumor cells resulted in an increase of apoptosis and inhibition of tumorigenesis. These results identify the E2f2 locus as a tumor suppressor through its ability to modulate apoptosis.

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    • "More recently, however, overexpression of E2F2 was reported to induce p53-mediated apoptosis of mouse retina neurons lacking Rb and p107, independent of other activating E2Fs (11). In a conditional bitransgenic mouse model of Myc-induced T-cell lymphomagenesis, Opavsky et al (12) demonstrated that inactivation of E2F2 (either E2F2+/− or E2F2−/−), but not of E2F1 or E2F3, significantly accelerated tumor onset and progression, indicating an haploinsufficient tumor suppressor function for E2F2 in T cells. Similar results were obtained with MMTV-Myc transgenic mice, in which E2F2 knockout delayed latency and reduced the incidence of Myc-driven mammary tumors (13). "
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    ABSTRACT: In a previous genome-wide expression profiling study, we identified E2F2 as a hyperexpressed gene in stem-like cells of distinct glioblastoma multiforme (GBM) specimens. Since the encoded E2F2 transcription factor has been implicated in both tumor suppression and tumor development, we conducted a functional study to investigate the pertinence of E2F2 to human gliomagenesis. E2F2 expression was knocked down by transfecting U87MG cells with plasmids carrying a specific silencing shRNA. Upon E2F2 silencing, in vitro cell proliferation was significantly reduced, as indicated by a time-course analysis of viable tumor cells. Anchorage-independent cell growth was also significantly inhibited after E2F2 silencing, based on cell colony formation in soft agar. Subcutaneous and orthotopic xenograft models of GBM in nude mice also indicated inhibition of tumor development in vivo, following E2F2 silencing. As expression of the E2F2 gene is associated with glioblastoma stem cells and is involved in the transformation of human astrocytes, the present findings suggest that E2F2 is involved in gliomagenesis and could be explored as a potential therapeutic target in malignant gliomas.
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    • "The transcription factor E2F2 has been implicated as a tumor suppressor protein and repressor of T lymphocyte proliferation [46], [47]. It stimulates apoptosis, and its disruption accelerates S phase entry and cell division [48], [49]. Based on this analysis, it could be assumed that the increased expression of E2F2 was one of the reasons for the induction of apoptotic cell death in SKW-3 cells in our study. "
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    ABSTRACT: Erufosine is a new antineoplastic agent of the group of alkylphosphocholines, which interferes with signal transduction and induces apoptosis in various leukemic and tumor cell lines. The present study was designed to examine for the first time the mechanism of resistance to erufosine in malignant cells with permanently reduced expression of the retinoblastoma (Rb) protein. Bearing in mind the high number of malignancies with reduced level of this tumor-suppressor, this investigation was deemed important for using erufosine, alone or in combination, in patients with compromised RB1 gene expression. For this purpose, clones of the leukemic T-cell line SKW-3 were used, which had been engineered to constantly express differently low Rb levels. The alkylphosphocholine induced apoptosis, stimulated the expression of the cyclin dependent kinase inhibitor p27Kip1 and inhibited the synthesis of cyclin D3, thereby causing a G2 phase cell cycle arrest and death of cells with wild type Rb expression. In contrast, Rb-deficiency impeded the changes induced by eru-fosine in the expression of these proteins and abrogated the induction of G2 arrest, which was correlated with reduced antiproliferative and anticlonogenic activities of the compound. In conclusion, analysis of our results showed for the first time that the Rb signaling pathway is essential for mediating the antineoplastic activity of erufosine and its efficacy in patients with malignant diseases may be predicted by determining the Rb status.
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    • "Other known tumor suppressor loci also carry disrupting insertions including NfI (20 insertions), Ovca2 (6) and Wwox (7). Candidates of particular note are: E2f2 (which can act as a haploinsufficient tumor suppressor of Myc-induced lymphoma in mice (Opavsky et al., 2007)), Raptor (a binding partner and inhibitor of mTOR (target of rapamycin) (Kim et al., 2002; Hara et al., 2002)), Nfatc3 (found in a previous retroviral screen to suppress SL3-3 induced lymphoma (Glud et al., 2005) and also found to suppress mammary adenocarcinoma (Lee et al., 2005)), Xrcc6 (Ku70) (knockouts of which develop thymic and disseminated T cell lymphomas [Li et al., 1998]) and Ablim1, which is located in a chromosomal region frequently lost in human tumors (Kim et al., 1997)(Figure S6). Notably, we observe few inserts within commonly mutated tumor suppressors such as Cdkn2a, Pten and Rb1. "
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