Complex Cartography: Regulation of E2F Transcription Factors by Cyclin F and Ubiquitin

Abstract

The E2F family of transcriptional regulators sits at the center of cell cycle gene expression and plays vital roles in normal and cancer cell cycles. Whereas control of E2Fs by the retinoblastoma family of proteins is well established, much less is known about their regulation by ubiquitin pathways. Recent studies placed the Skp1-Cul1-F-box-protein (SCF) family of E3 ubiquitin ligases with the F-box protein Cyclin F at the center of E2F regulation, demonstrating temporal proteolysis of both activator and atypical repressor E2Fs. Importantly, these E2F members, in particular activator E2F1 and repressors E2F7 and E2F8, form a feedback circuit at the crossroads of cell cycle and cell death. Moreover, Cyclin F functions in a reciprocal circuit with the cell cycle E3 ligase anaphase-promoting complex/cyclosome (APC/C), which also controls E2F7 and E2F8. This review focuses on the complex contours of feedback within this circuit, highlighting the deep crosstalk between E2F, SCF-Cyclin F, and APC/C in regulating the oscillator underlying human cell cycles.

Keywords: APC/C (Cdh1); E2F; SCF (Cyclin F); cell cycle; transcription; ubiquitin.

Figure 1.

A schematic illustration of relationships and feedback mechanisms between the E2F1-E2F7/8 transcriptional circuit and the SCF^{Cyclin F}-APC/C degradational circuit across cell cycle milestones. In G1-phase (top-left), APC/C and E2F1 are active. E2F1 drives the expression of cell cycle genes that ultimately promote S-phase entry, and also E2F7/8 which will ultimately extinguish its own activity. APC/C promotes the ubiquitination and degradation of many proteins, including the cell cycle transcription factor FoxM1, the SCF substrate receptor Cyclin F, and E2F7/8. In S-phase, APC/C is inactivated by several mechanisms, including the degradation of Cdh1 by SCF-Cyclin F. Since APC/C is inactive, E2F7/8 can inhibit the expression of E2F1 target genes. Cyclin F also inhibits B-Myb in response to DNA damage, although this inhibition is not through degradation. In G2-phase, Cyclin F protein levels peak and SCF-Cyclin F triggers the destruction of E2F1 (and E2F2/3) and E2F7/8. B-Myb and FoxM1 transcription factors are both fully active and promote the expression of Cyclin F and Cdh1. Finally, cells progress through and exit mitosis, APC/C becomes active and the system is reset.