Do negative feedback oscillations drive variations in the length of the tumor cell division cycle?

The cell cycle length of individual cells within a tumor cell population is known to vary, mainly as a consequence of differences in the length of G1 phase. A number of observations suggest that the distribution of G1 phase transit times is well described by models where the transition from G1 to S phase is governed by a probability mechanism. However, entry into S phase as a consequence of progressive accumulation of cyclin E with time, to the point where cyclin-dependent kinase-2 (cdk2) is activated, does not provide a basis for a probability mechanism. We suggest that oscillation of the activity of the E2F-1 transcription factor during G1 phase could provide a mechanism that explains the kinetic behavior of G1 phase cells. A negative feedback loop controlling oscillation is possible because activation of cdk2, following activation by cyclin E, phosphorylates the E2F-1 transcription factor, marking it for ubiquitination by the Skp2-cullin-F-box complex and subsequent proteolytic removal. The activity of several cellular transcription factors, including p53 and NF-kappaB, has been shown to oscillate by negative feedback loops leading to ubiquitination and subsequent proteolytic degradation. The oscillatory mechanisms for p53 and NF-kappaB suggest that transitions from the cell cycle to apoptosis are also governed by probability functions.