Irreversible Transitions, Bistability and Checkpoint Controls in the Eukaryotic Cell Cycle: A Systems-Level Understanding - Systems Biology Concepts and Insights - page 257

TABLE 14.2 Molecular Components of the Cell Cycle Control System

Typical Reaction a , b

Name Yeast Ortholog Description

Cdk1, Cdk2, . Cdc28 Cylin-dependent kinase Protein þ ATP / Protein-P þ ADP; Cdkn:CycX

CycA Clb5, Clb6 S-phase promoting cyclin ORC / ORC-P; Cdk2:CycA

CycB Clb1, Clb2 M-phase promoting cyclin Histone / Histone-P; Cdk1:CycB

CycD Cln3 Growth-responding cyclin RB RB-P; Cdk4:CycD

/

CycE Cln1, Cln2 Starter kinase CKI CKI-P; Cdk2:CycE

/

CAP Counter-acting phosphatase Protein-P þ H 2 O Protein þ P i ;CAP

/

CKI Sic1 Cdk stoichiometric inhibitor Cdk1:CycB þ CKI CKI: Cdk1:CycB

/

Cohesin Scc1, etc. Sister-chromatid cohesion Xsome Xtid: Cohesin: Xtid; S phase

/

Separase Esp1 Cohesin degradation Cohesin DP; Separase

/

Securin Pds1 Separase inhibitor Separase þ Securin Securin: Separase

4

APC APC Anaphase promoting complex Securin: Separase Separase þ DP; APC:Cdc20

/

Cdc20 Cdc20 Targeting subunit of APC APC þ Cdc20 APC:Cdc20

4

Cdh1 Hct1 Homolog of Cdc20 Cdk1:CycB Cdk1 þ DP; APC:Cdh1

/

SCF SCF Skp-Cullin-Fbox complex CKI-P DP; SCF

/

Mad2 Mad2 Inhibitor of APC:Cdc20 APC:Cdc20 þ Mad2 A / MCC

Cdc14 Exit phosphatase APC:Cdh1-P / APC:Cdh1; Cdc14

Net1 Inhibitor of Cdc14 Net1 þ Cdc14 4 Net1:Cdc14

E2F SBF Transcription factor CYCE promoter þ E2F 4 CYCE:E2F (active gene)

RB Whi5 Inhibitor of E2F RB þ E2F 4 RB:E2F

Wee1 Swe1 Tyrosine kinase Cdk1:CycB P-Cdk1:CycB; Wee1

/

Cdc25 Mih1 Tyrosine phosphatase P-Cdk1:CycB Cdk1:CycB; Cdc25

/

a A

þ B / C þ D; E denotes a chemical reaction and its catalyzing enzyme. Reversible binding reactions are indicated by 4 .

b Orc, origin of replication complex; DP, degradation products; MCC, mitotic checkpoint complex.

speculations about the cell cycle will begin to make sense.
And as we begin to understand the molecular logic of cell
cycle control, we can expect to parlay this knowledge into
significant advances in human health, agricultural produc-
tivity and biotechnological innovations.

irreversible. What sort of molecular interactions account for
this directionality?
It is an alluring fact that at each irreversible transition of
the cell cycle an important regulatory protein is degraded
( Figure 14.1 ). At the G1/S transition, the CKI that was
inhibiting CDK activity throughout G1 phase is rapidly
degraded. At the G2/M transition, the Wee1 kinase that was
inhibiting CDK activity throughout G2 phase is rapidly
degraded [44] . At the M/A transition, the cohesin rings that
were holding sister chromatids together prior to metaphase
are cleaved by separase. As cells exit mitosis and return to
G1, cyclin B subunits, which played essential roles in
orchestrating mitosis, are degraded by the APC. These
observations have led many commentators to suggest that
proteolysis is the basis of irreversibility ( Table 14.3 ). Is
proteolysis one of the fundamental principles of cell cycle
regulation that we are seeking?

IRREVERSIBILITY AND BISTABILITY
Irreversible progression through the cell cycle means that
S and M phases always occur in strict alternation, separated
by gaps e G1 and G2. When functioning properly, the cell
cycle moves steadily forward like a ratchet device, not
slipping backwards, say, to do two rounds of DNA synthesis
without an intermediate mitosis. Of course, this happens
sometimes, in cells under stress or in mutant cells [42] ,or
even by design (in terminally differentiated polyploid cells)
[43] , but in general mitotic cell cycle transitions are