Disease relevance of E2f3

• E2F3 loss has opposing effects on different pRB-deficient tumors, resulting in suppression of pituitary tumors but metastasis of medullary thyroid carcinomas [1].
• In contrast, E2F-3 expression is up-regulated as retinoblasts differentiate into the ganglion cell layer [2].
• Here, we show that directed expression of E2F2 and E2F4 by adenovirus mediated gene transfer in neonatal cardiomyocytes induced S-phase entry but did not result in an onset of apoptosis whereas directed expression of E2F1 and E2F3 strongly evoked programmed cell death concomitant with cell cycle progression [3].

High impact information on E2f3

• This rescue appears to be cell autonomous since the inactivation of Rb and E2f3 in TS cells restored placental development and extended the life of embryos to E17 [4].
• Arf loss also rescues the known cell cycle re-entry defect of E2f3(-/-) cells, and this correlates with restoration of appropriate activation of classic E2F-responsive genes [5].
• Repression of the Arf tumor suppressor by E2F3 is required for normal cell cycle kinetics [5].
• Thus, contrary to the prevailing view of E2F action, E2F3 makes a major contribution to the apoptosis resulting from pRB loss [6].
• E2f3 is critical for normal cellular proliferation [7].

Biological context of E2f3

• Mutation of E2f3 dramatically impairs the mitogen-induced, transcriptional activation of numerous E2F-responsive genes [7].
• Here we show that E2F3 also has a significant effect on the phenotype of tumor-prone Rb(+/-) mice [1].
• We also identified patterns of gene expression that specifically differentiate the activity of E2F1 and E2F3; this profile is enriched in genes known to function in mitosis [8].
• Gene expression profiles that distinguish either E2F1- or E2F3-expressing cells from quiescent cells are enriched in genes encoding cell cycle and DNA replication activities, consistent with many past studies [8].
• In contrast to the E2F3a product that is tightly regulated by cell growth, the E2F3b product is expressed equivalently in quiescent and proliferating cells [9].

Anatomical context of E2f3

• We now demonstrate that E2f1, E2f2, and E2f3 are also required for oncogene-mediated transformation of mouse embryonic fibroblasts [10].
• Finally, we show that E2F3 is not required for cellular immortalization but is rate limiting for the proliferation of the resulting tumor cell lines [7].
• Uncloned pools of NIH 3T3 cells producing the pRB binding target E2F-1, E2F-2, or E2F-3 grew in semisolid medium [11].
• Chromatin immunoprecipitation analysis demonstrated that the cyclin A promoter is predominantly bound in proliferating keratinocytes by complexes containing E2F-3 and E2F-4 [12].
• Inactivation of E2F3 results in centrosome amplification [13].

Associations of E2f3 with chemical compounds

• As opposed to UVB-exposed skin, UVB-induced tumors showed elevated levels of E2F1, but these were reduced in silibinin-treated tumors without any effect on E2F2 and E2F3 [14].

Physical interactions of E2f3

• Furthermore, Rb -/- cells surviving in vitro exhibit an upregulation of p107 that is found in complexes with E2F3 [15].

Regulatory relationships of E2f3

• E2F3 loss suppresses the development of the pituitary tumors that normally account for the death of Rb(+/-) mice [1].
• We now show that additional E2F target genes share a common promoter architecture and are also regulated by the combined action of TFE3 and E2F3 [16].
• In contrast, the thymidine kinase (TK-1) promoter is also regulated by E2F3 but independent of TFE3 [16].

Other interactions of E2f3

• E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos [6].
• Consistent with this notion, Arf mutation suppresses the activation of p53 and p21(Cip1) in E2f3-deficient MEFs [5].

References