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The atypical E2Fs, E2F7 and E2F8, act as potent transcriptional repressors of DNA replication genes providing them with the ability to induce a permanent S‐phase arrest and suppress tumorigenesis. Surprisingly in human cancer, transcript levels of atypical E2Fs are frequently elevated in proliferating cancer cells, suggesting that the tumor suppressor functions of atypical E2Fs might be inhibited through unknown post‐translational mechanisms. Here, we show that atypical E2Fs can be directly phosphorylated by checkpoint kinase 1 (Chk1) to prevent a permanent cell cycle arrest. We found that 14‐3‐3 protein isoforms interact with both E2Fs in a Chk1‐dependent manner. Strikingly, Chk1 phosphorylation and 14‐3‐3‐binding did not relocate or degrade atypical E2Fs, but instead, 14‐3‐3 is recruited to E2F7/8 target gene promoters to possibly interfere with transcription. We observed that high levels of 14‐3‐3 strongly correlate with upregulated transcription of atypical E2F target genes in human cancer. Thus, we reveal that Chk1 and 14‐3‐3 proteins cooperate to inactivate the transcriptional repressor functions of atypical E2Fs. This mechanism might be of particular importance to cancer cells, since they are exposed frequently to DNA‐damaging therapeutic reagents.

Programmed polyploidization occurs in all mammalian species during development and aging in selected tissues, but the biological properties of polyploid cells remain obscure. Spontaneous polyploidization arises during stress and has been observed in a variety of pathological conditions, such as cancer and degenerative diseases. A major challenge in the field is to test the predicted functions of polyploidization in vivo. However, recent genetic mouse models with diminished polyploidization phenotypes represent novel, powerful tools to unravel the biological function of polyploidization. Contrary to a longstanding hypothesis, polyploidization appears to not be required for differentiation and has no obvious impact on proliferation. Instead, polyploidization leads to increased cell size and genetic diversity, which could promote better adaptation to chronic injury or stress. We discuss here the consequences of reducing polyploidization in mice and review which stress responses and molecular signals trigger polyploidization during development and disease.

Recently, we showed that E2F7 and E2F8 (E2F7/8) are critical regulators of angiogenesis through transcriptional control of VEGFA in cooperation with HIF. (1) Here we investigate the existence of other novel putative angiogenic E2F7/8-HIF targets, and discuss the role of the RB-E2F pathway in regulating angiogenesis during embryonic and tumor development.