Throughout embryogenesis and adult life, cells respond to extracellular signals and developmental programs by proliferating, differentiating, becoming quiescent or dying. These signals direct the cell cycle machinery to change course, often by regulating the activity of the retinoblastoma tumor suppressor family of transcriptional regulators (pRB, p107 and p130), which bind numerous cellular proteins, among which are the E2F/DP transcription factors. E2F/DP transcriptional activity results from the heterodimerization of an E2F (E2F-1,-2, -3, -4, -5 or -6) with a DP (DP-1,or -2) protein. E2F/DP-dependent target genes include many genes intimately involved in cell cycle progression, such as proto-oncogenes, S-phase genes, pRB family genes and some of the E2F genes themselves. During G0/G1, E2F/DP-dependent transactivation is repressed by the direct interaction of E2F/DP heterodimers with pRB family members at target promoters. During the G1 to S transition, E2F/DP heterodimers are released from pRB family-mediated repression, allowing E2F/DP-dependent transactivation of target genes and cell cycle progression.
Previously, it has been shown that overexpression of E2F/DP transcriptional activity has vastly different effects on cells, in some settings leading to proliferation and in other cases leading to p53-mediated apoptosis. To understand how E2F/DP transcriptional activity functions in vivo and how it regulates proliferation, differentiation, quiescence and/or apoptosis, we have inactivated E2F transcriptional activity in two distinct ways using mouse knock-out technology. First, we have inactivated E2F-1, the best characterized E2F family member to-date. Second, we have inactivated DP-1, the most abundant DP family member yet described.
Despite the apparent biochemical redundancy within the E2F and DP transcription factor families in tissue culture models, inactivation of specific E2F and DP family members has dramatic consequences in vivo. E2F-1 deficient mice are viable, yet develop a range of tumors (e.g. lung adenocarcinoma, reproductive tract sarcoma and lymphoma) and tissue-specific atrophy midway through adult life. At this time, the mechanism of tumorigenesis in the E2F-1 deficient mice is not known and may be due to a loss of pRB-mediated tumor suppression, a lack of p53-mediated apoptosis or perhaps an inability to differentiate. In stark contrast, the DP-1 deficient mice die as embryos midway through gestation. These strikingly different phenotypes of the E2F-1 deficient or DP-1 deficient mice demonstrate that E2F/DP-transcriptional activity has many and often opposing roles in vivo, and furthermore that these roles are tissue-specific as well as temporally specific. Additionally, we have shown that inactivation of E2F-1 inhibits pituitary and thyroid tumor formation driven by the loss of pRB, which demonstrates that E2F-1 acts downstream of pRB in these tumors. Currently we are investigating the mechanism(s) by which inactivation of E2F-1 or DP-1 leads to such radically different outcomes.
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