The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 241

mice. 22,124,126,149,166,167 Thus, cell cycle clock can function independent of
the molecular clock. However, the control of the expression of key cell cycle
genes by an intact molecular clock is indispensable for coupling the rate of
cell proliferation to diurnal changes in mammalian physiology in vivo .
Both positive and negative loops of the molecular clock are involved in
circadian control of cell cycle gene expression in peripheral tissues. The
best-studied clock-controlled cell cycle regulators include oncogenes c-Myc ,

Mdm2 ,and b-catenin , Cyclins D1 , B ,and A , and tumor suppressors p53 ,

Wee1 ,and p21 WAF1/CIP1 . 82,124,126,149,166,179 c-Myc is an immediate early

responsive gene to diverse cell proliferation stimuli. It plays a key role in G1
cell cycle initiation aswell as cell growth and death ( Fig. 9.1 ). 222 The expression
of c - Myc is tightly controlled in somatic cells in response to diverse stimuli at the
transcriptional level via multiple cis -acting sequences in its proximal promoter
region. 223 Deregulation of c-Myc in cooperation with loss of function in p53
promotes neoplastic transformation, and tumor initiation, maintenance, and
metastasis. 224 In addition to clock-controlled chromatin remodeling,
BMAL1/CLOCK and BMAL1/NPAS2 directly regulate c-Myc transcription
via the two E-boxes in the P1 promoter of c-Myc . 124,149,225 Disruption of cir-
cadian rhythm leads to deregulation of c-Myc which is coupled with increased
neoplastic growth inmice, suggesting that the control of G1 cell cycle initiation
is one of the key mechanisms for circadian control of tumor suppres-
sion. 29,124,149 Many key cell cycle regulators, such as Cdk4 , Itga6 , Wnt3 ,
LHx2 , Tcf4 , Sox 9 , Smad7 ,and Wee1 are also directly regulated at the transcrip-
tional level byBMAL1/CLOCKheterodimer via E-box-mediated interaction
in the gene promoters. 126,167,225 p53 and MDM2 are controlled indirectly by
the Per genes via the tumor suppressor ataxia-telangiectasia mutated (ATM) at
the posttranscriptional level. 29,82 Bmal1 has also been reported to regulate

p53- p21 WAF1/CIP1 signaling, although the molecular mechanism of this reg-
ulation is still not clear. 69,92,179 The rhythmic expression of cell cycle genes and
tumor suppressor p53 is synchronized with the oscillation patterns of the core
circadian genes in normal somatic tissues in both humans and mouse
models. 29,124,126,226-228
The core circadian regulators also regulate the activity of b -Catenin via
direct control of intracellular signaling pathways. Constitutive activation of
the core circadian regulator CKI e mimics the effect of WNT signaling,
resulting in cytoplasmic accumulation of b -Catenin and its subsequent
nuclear localization. 229,230 In the nucleus, b -Catenin interacts with tran-
scription factors of the T-cell-specific transcription factor/lymphoid
enhancer factor-1 (TCF/LEF) family to regulate transcription and promote
tumorigenesis. 231,232 Genes activated by b -Catenin/TCF/LEF include