The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 235

Figure 9.1 Control of cell proliferation by the molecular clock. Unlike the molecular
clock, the cell cycle does not free-run before passing the G1/S-phase transition. The ini-
tiation of cell cycle progression is strictly controlled by extracellular mitogenic signals
that transiently activate immediate early genes such as c-Myc, which then induces Cyclin
D leading to activation of Cyclin D/CDK4/6 complex that in turn activates E2F-
dependent Cyclin E expression by suppressing tumor suppressor RB (not shown).
The interaction of Cyclin E with CDK2 allows G1- to S-phase transition. G1 is the longest
phase in the cell cycle during which most biosynthesis essential for supporting cell cycle
progression occurs. c-MYC or E2F oncogenic activation-induced elevation of G1 Cyclin
expression or genomic DNA damage leads to activation of G1 checkpoint mediated by
p16 Ink4A and p21 WAF1/CIP1 , controlled by RB and p53, respectively. p16 Ink4A disrupts
Cyclin D/CDK4/6 complex (not shown), whereas p21 WAF1/CIP1 disrupts Cyclin E/CDK2
interaction. The activation of G1 checkpoint leads cells to pause before entering the
S phase to repair damaged DNA or exit the cell cycle to enter the G0 phase (nondividing
status). Under certain conditions, excessive DNA damage or uncontrolled oncogenic
signaling can activate RB and/or p53 tumor suppression pathways leading to cellular
senescence. DNA damage induced by UV radiation leads to activation of ATR/CHK1-
mediated intra-S checkpoint that couples DNA damage repair with replication whereas
double-stranded DNA damage induced by g-radiation activates ATM/CHK2-mediated
G1/S and G2/M checkpoints to prevent damaged cells from entering the S or mitotic
(M) phase. Prolonged G2/M checkpoint arrest is also often associated with p53-
mediated apoptosis. G2/M transition is also regulated by WEE1, a kinase that phosphor-
ylates and inactivates the Cyclin B1/cell division cycle 2 (CDC2) complex essential for
G2/M transition. Upon the completion of mitosis, cells either enter the next cell cycle
stimulated by extracellular mitogen, or withdraw from cell cycle to enter the G0 phase
in the absence of mitogenic signals . 173,174 The molecular clock functions in all phases of
the cell cycle to prevent neoplastic growth. At the early G1 phase, the BMAL1/CLOCK
heterodimer downregulates Myc transcription to prevent its overexpression . 29,124,149
PER1 directly interacts with ATM and CHK2 to control G1 checkpoint in response to
double-strand DNA damage . 82 In the S phase, CRY2/TIM complex directly interacts with
ATR/CHK1 to control intra-S checkpoint. 175 In the G2 phase, PER-mediated ATM/CHK2/
p53 signaling in response to DNA double-strand breaks and BMAL1/CLOCK activated
Wee1 expression both lead to activation of G2/M checkpoint to prevent inappropriate
M phase entry . 82,126