%0 Journal Article
%T Quantitative Systems Biology to decipher design principles of a dynamic cell cycle network: the ※Maximum Allowable mammalian Trade每Off每Weight§ (MAmTOW)
%A Matteo Barberis
%A Paul Verbruggen
%J Archive of "NPJ Systems Biology and Applications".
%D 2017
%R 10.1038/s41540-017-0028-x
%X Schematic representation of processes occurring throughout cell cycle progression, exemplified by the role of the cyclin-dependent kinase inhibitor p27Kip1 (p27). a In quiescent cells, p27 accumulates and inactivates cyclin E/Cdk2 complexes每deputed to promote DNA replication at the G1/S transition-by sequestering them in a 1:1 stoichiometry and blocking their kinase activity (Supplementary References 1,2). b Mitogenic stimulation of quiescent cells leads to nuclear export of p27 mediated by cyclin D2 (Supplementary Reference 3) and the nuclear export protein CRM1 (not visualized) (Supplementary Reference 4). c Export of p27 is coincidental with its phosphorylation on Ser10 (Supplementary Reference 5) by KIS (Supplementary Reference 6) and possibly PKB/Akt (Supplementary Reference 7) kinases. d Upon cytoplasmic translocation, p27 is ubiquitylated and degraded through interaction with KPC ubiquitin ligase complexes (not visualized), reducing p27 protein content in both nuclear and cytoplasmic compartments through export and by degradation, respectively (Supplementary Reference 8). e Nuclear p27 is reduced further during the G0/G1 transition through its direct phosphorylation on Thr157 by cytoplasmic Akt kinase, preventing both de novo produced and exported p27 from (re)entering the nucleus (Supplementary References 9每11). Cytoplasmic translocation, degradation and p27 exclusion from the nucleus lead to a first wave of active cyclin/Cdk kinase complexes that allow entry of cells in G1 phase. During this phase, p27 regulation is altered: f activation of Cdk2 leads to phosphorylation of p27 on Thr187 and g recognition by the SCF(Skp2) ubiquitin ligase complex, which is followed by rapid degradation of p27 in the nucleus (Supplementary References 1,12). h This process leads to release of the inhibition of cyclin E/Cdk2 complexes and progression into S phase. i During S phase, Cdk2 continues to phosphorylate p27 on Thr187 and, in turn, SCF(Skp2) keeps p27 at low levels in the nucleus (Supplementary References 1,4,13每15
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605530/