Swat, Maciej;Kel, Alexander;Kel-Margoulis, Olga;Deineko, Oleg;Herzel, Hanspeter - Modeling the influence of feedback loops on the G1/S transition

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Title: Modeling the influence of feedback loops on the G1/S transition	P159
Swat, Maciej; Kel, Alexander; Kel-Margoulis, Olga; Deineko, Oleg; Herzel, Hanspeter swat@itb.biologie.hu-berlin.de Institute for Theoretical Biology

Modeling the cell cycle of yeast and eukaryots became very intensively studied topic in recent years, e.g. [ 4/5], [1], [2].
The cell cycle is usually divided in four phases (G1->S->M->G2): S-phase (Synthesis - DNA replication), M-phase (Mitosis - Chromosome Separation) and two gaps between them, G1 and G2. Two points during the loop are of particular importance, so called checkpoints, one before the G1/S and the other before G2/M transition.
Checkpoints block entry to the next stage if the previous step is incomplete, or the signal to progress is insufficient.
We present a model for the G1/S transition in eukaryotic cells, which includes a set of proteins and their gene regulatory network. It is based on a model proposed by [3] and includes the core proteins responsible for progression from G1- to S-phase of cell cycle, such as:

1. pRB (Retinoblastoma) - tumor suppressor from the family of pocket proteins (pRB, p107, p130),
2. E2F1 - transcription factor targeting genes that regulate cell cycle progression (cyclins and cyclin-dependent kinases, cdc25A, E2F1, histones, Myc and Myb-transcription factors, DNA replication proteins etc.),
3. AP-1 - family of transcription factors (heterodimers of Fos and Jun family proteins) that mediate mitogenic signals,
4. Cyclin D/cdk4,6 and Cyclin E/cdk2 - complexes, which levels vary during the cell cycle, characterising the G1- and S-phase,
5. p53 - transcription factor / tumor suppressor with its counterpart mdm2.
The aim was to verify former results in the new system, drawing some conclusions about the role of feedback loops in the wild-type cells and discussion of abnormal changes that occur as the consequence of activation of p53.

[1] Aguda BD, Tang Y., The kinetic origins of the restriction point in the mammalian cell cycle, Cell Prolif. 1999 Oct;32(5):321-35.
[2] Kaern M, Hunding A., Dynamics of the cell cycle engine: Cdk2-kinase and the transition into mitosis, J Theor Biol. 1998 Jul 7;193(1):47-57.
[3] Kel et.al. Modeling of gene regulatory network of cell cycle control. Role of E2F feedback loops, 2000, GCB00.
[4] Tyson JJ, Chen K., Novak B. Network dynamics and cell physiology, Nat Rev Mol Cell Biol. 2001 Dec;2(12):908-16.
[5] Tyson JJ, Novak B. Regulation of the eukaryotic cell cycle: molecular antagonism, hysteresis, and irreversible transitions, J. Theor. Biol. 2001 May 21;210(2):249-63.