PMID- 23230424
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20121212
LR  - 20211021
IS  - 1664-042X (Electronic)
IS  - 1664-042X (Linking)
VI  - 3
DP  - 2012
TI  - Double-negative feedback between S-phase cyclin-CDK and CKI generates abruptness 
      in the G1/S switch.
PG  - 459
LID - 10.3389/fphys.2012.00459 [doi]
LID - 459
AB  - The G1/S transition is a crucial decision point in the cell cycle. At G1/S, there 
      is an abrupt switch from a state of high cyclin-dependent kinases (CDK) inhibitor 
      (CKI) levels and low S-phase CDK activity to a state of high S-phase CDK activity 
      and degraded CKI. In budding yeast, this transition is triggered by 
      phosphorylation of the Cdk1 inhibitor Sic1 at multiple sites by G1-phase CDK 
      (Cln1,2-Cdk1) and S-phase CDK (Clb5,6-Cdk1) complexes. Using mathematical 
      modeling we demonstrate that the mechanistic basis for the abruptness of the G1/S 
      transition is the highly specific phosphorylation of Sic1 by S-phase CDK complex. 
      This switch is generated by a double-negative feedback loop in which S-CDK1 
      phosphorylates Sic1, thus targeting it for destruction, and thereby liberating 
      further S-CDK1 from the inhibitory Sic1-S-CDK1 complex. Our model predicts that 
      the abruptness of the switch depends upon a strong binding affinity within the 
      Sic1-S-CDK inhibitory complex. In vitro phosphorylation analysis using purified 
      yeast proteins revealed that free Clb5-Cdk1 can create positive feedback by 
      phosphorylating Sic1 that is bound in the inhibitory complex, and that Sic1 
      inhibits Clb5-Cdk1 with a sub-nanomolar inhibition constant. Our model also 
      predicts that if the G1-phase CDK complex is too efficient at targeting Sic1 for 
      destruction, then G1/S becomes a smooth and readily reversible transition. We 
      propose that the optimal role for the G1-phase CDK in the switch would not be to 
      act as a kinase activity directly responsible for abrupt degradation of CKI, but 
      rather to act as a priming signal that initiates a positive feedback loop driven 
      by emerging free S-phase CDK.
FAU - Venta, Rainis
AU  - Venta R
AD  - Institute of Technology, University of Tartu Tartu, Estonia.
FAU - Valk, Ervin
AU  - Valk E
FAU - Koivomagi, Mardo
AU  - Koivomagi M
FAU - Loog, Mart
AU  - Loog M
LA  - eng
PT  - Journal Article
DEP - 20121206
PL  - Switzerland
TA  - Front Physiol
JT  - Frontiers in physiology
JID - 101549006
PMC - PMC3515773
OTO - NOTNLM
OT  - CDK
OT  - CKI
OT  - Cdk1
OT  - G1/S
OT  - Sic1
OT  - cell cycle
OT  - cyclin-dependent kinases
OT  - switch
EDAT- 2012/12/12 06:00
MHDA- 2012/12/12 06:01
PMCR- 2012/12/06
CRDT- 2012/12/12 06:00
PHST- 2012/10/04 00:00 [received]
PHST- 2012/11/19 00:00 [accepted]
PHST- 2012/12/12 06:00 [entrez]
PHST- 2012/12/12 06:00 [pubmed]
PHST- 2012/12/12 06:01 [medline]
PHST- 2012/12/06 00:00 [pmc-release]
AID - 10.3389/fphys.2012.00459 [doi]
PST - epublish
SO  - Front Physiol. 2012 Dec 6;3:459. doi: 10.3389/fphys.2012.00459. eCollection 2012.