title: Do negative feedback oscillations drive variations in the length of the tumor cell division cycle?
abstract: 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.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. b.baguley@auckland.ac.nz
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Baguley
authors.forename: Elaine
authors.initials: E
authors.lastname: Marshall
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005246:Feedback; D016193:G1 Phase / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016196:S Phase / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D019927:Cyclin E; D050687:E2F1 Transcription Factor; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D051357:Cyclin-Dependent Kinase 2