Cell Cycle Regulation

1
Cell Cycle Regulation
The cell cycle is regulated by cyclins,
cyclin-dependent kinases (CDKs), and
cyclin-dependent kinase inhibitors (CDKIs) and is
divided into 4 distinct phases (G1, S, G2, and
M). G0 represents exit from the cell cycle. The
cell cycle is driven by CDKs, which are
positively and negatively regulated by cyclins
and CDKIs, respectively. The restriction point
governs the transition point beyond which
progression through the cell cycle is independent
of external stimuli. Adapted from Shah and
Schwartz. Clin Cancer Res. 200172168-2181, with
permission.
2
Rb and the G1-S Transition
Retinoblastoma gene product (Rb) governs entry
into S phase. Hypophosphorylated Rb forms a
complex with a group of transcription factors,
E2F. When Rb is inactivated by CDK2-, CDK4-, or
CDK6-mediated phosphorylation, E2F transcription
factors are released, resulting in progression
into S phase and transcription of a range of
targets involved in chemotherapy sensitivity.
Adapted from Shah and Schwartz. Clin Cancer Res.
200172168-2181, with permission.
3
Apoptosis
Members of the Bcl-2 family of proteins may be
either antiapoptotic (Bcl-2, Bcl-xL, Mcl-1) or
proapoptotic (BAD, Bax, Bak, and others). Bcl-2
and Bcl-xL bind and inhibit Apaf-1 and prevent
caspase activation. In the presence of excess
Bax, Bcl-2 is displaced from Apaf-1, allowing
caspase cleavage and activation. Bax further
promotes apoptosis by mediating the release of
cytochrome c (Cyto c) from mitochondria Cyto c
activates Apaf-1 and caspase 9 and the cascade of
activation of effector caspases, resulting in the
cleavage of multiple cellular proteins. From Shah
and Schwartz. Clin Cancer Res. 200172168-2181,
with permission.
4
Cell Cycle Inhibitors
Flavopiridol
UCN-01
Bryostatin-1
5
Cell Cycle Inhibition by Flavopiridol
Flavopiridol is a pancyclin-dependent kinase
(CDK) inhibitor of CDK1 (Cdc2), CDK2, CDK4, and
CDK6 at nanomolar concentrations, resulting in
cell cycle arrest at both the G1/S and the G2/M
transitions.
6
Cell Cycle Inhibition by UCN-01
UCN-01 has cell cycle effects at both the G1/S
and G2/M transitions. At G1/S, UCN-01
hypophosphorylates Rb and causes the destruction
of free E2F-1 by ubiquitination and targeting for
proteasome degradation. The net effect is arrest
in G1 and significant reduction in early S-phase
proteins. At the G2/M transition, through
inhibition of Chk1, UCN-01 increases the activity
of cyclin B/Cdc2, resulting in G2 checkpoint
abrogation and premature entry into M.
7
Cell Cycle Inhibition by Bryostatin-1
Bryostatin-1 transiently induces p21 and
subsequent dephosphorylation and inactivation of
CDK2. Bryostatin-1 also decreases expression of
cyclin B, preventing Cdc2 activation. The net
effect is G2 phase arrest of the cell cycle.