Diacylglycerol Signaling

158 J.D. Black
A and B (Malumbres and Barbacid 2005; Sanchez and Dynlacht 2005). At the end
of S-phase, cyclin A associates with Cdk1 to promote phosphorylation of several
proteins involved in DNA replication and cell cycle progression. During G , cyclin
2
A is degraded, while B-type cyclins are actively synthesized; Cdk1 thus associates
with cyclin B to trigger mitosis.
Multiple mechanisms control the activity of cyclin/Cdk complexes, including
degradation of cyclins, positive and negative phosphorylation events, and association
with CKIs. Positive phosphorylation of Cdks is mediated by Cdk activating
kinase (CAK or Cdk7/cyclin H) (Fisher and Morgan 1994), while negative phosphorylation
involves the kinases Wee1 and Myt1. Inhibitory phosphorylation is
removed by Cdc25 phosphatases, a necessary step for full kinase activity. Cdk
inhibition is also achieved by CKIs, which bind to cyclin/Cdk complexes and
render them inactive (Sherr and Roberts 1995). The Cip/Kip CKIs, which include
p21Waf1/Cip1 , p27Kip1 , and p57, inhibit cyclin E-, cyclin A- and cyclin B-dependent
activity (i.e., Cdk2 and Cdk1). Members of the INK4 family (p15, p16, p18, and
p19), on the other hand, are specific inhibitors of Cdk4 and Cdk6. Notably, p21Waf1/ Cip1 Kip1 and p27 act as positive regulators of cyclin D-dependent kinases (Sherr
and Roberts 1999).
Cell-cycle progression can be blocked at the G →S and G →M checkpoints as
1 2
well as in S phase and mitosis. Inhibitory pathways usually activate p21Waf1/Cip1 or
other CKIs, which block Cdk2 and/or Cdk1 activity. The balance between mitogenic,
antimitogenic, apoptotic, and stress response signals ultimately determines
cell fate and the ability to proliferate.
8.1.1.2 A Minimal Model of Cell Cycle Control
It should be noted that recent work with gene-targeted mice has revealed considerable
redundancy within the classical model of cell cycle regulation. It is now clear that
Cdks and cyclins have overlapping functions and that only a limited subset of these
molecules is absolutely required for control of cell cycle progression (Malumbres and
Barbacid 2005; Hochegger et al. 2008; Berthet and Kaldis 2007; Malumbres 2005).
Genetic evidence has demonstrated that (a) Cdk4, Cdk6, and Cdk2 are not required
for the mitotic cell cycle (Santamaria et al. 2007); (b) Cdk4/Cdk6 are not essential
for mitogen-induced entry into the cell cycle; and (c) the inhibitory and tumor
suppressor activities of the Cip/Kip CKIs can occur in the absence of Cdk2. However,
a strict requirement for these molecules has been noted in certain specialized cells:
Cdk2 is essential for the meiotic cell cycle in germ cells, Cdk4 is required in the
pancreas, and Cdk6 is critical for erythropoiesis.
On the basis of these findings, the following minimal model for cell cycle
control has emerged (Hochegger et al. 2008): any combination of Cdk1 or Cdk2,
partnered with nuclear cyclin E or cyclin A, is sufficient to trigger S phase.
Completion of S phase and entry into mitosis probably requires cyclin A, while
cyclin B is essential for raising the activity of Cdk1 above the threshold level
required for mitosis. It has been proposed that the difference between interphase