The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 242

members of the AP1 transcription family, c-Myc and Cyclin D1 . 233-238 Inter-
estingly, the molecular clock itself also responds to b -Catenin nuclear local-
ization to regulate the expression of genes via BMAL1/CLOCK-mediated
transcriptional regulation. 167 Aberrant activation of b -Catenin also disrupts
the molecular clock to promote neoplastic transformation by inducing
b -transducin repeat-containing protein-mediated PER2 degradation. 151
In the absence of WNT signaling, b -Catenin is destabilized by glycogen
synthase kinase-3 b (GSK3 b ), a functional homologue of the core circadian
gene Shaggy in the fruit fly, which functions in regulating the period length
of circadian cycles by indirectly controlling PER stability and nuclear
entry. 239,240 Recent studies have revealed that deregulation of GSK3 b
promotes tumor cell survival, proliferation, invasion, and resistance to
chemo- and radiation therapy in humans by inhibiting p53 andRB tumor sup-
pressors, inducing intracellular NF- k Bsignaling, Cyclin D1 overexpression,
and local chronic inflammation. 241,242 The activity of GSK3 b exhibits robust
circadian rhythm in both SCN and peripheral tissues, suggesting that GSK3 b
may also indirectly target PER2 in the mammalian molecular clock. 243
Together, the evidence discussed above suggests that the molecular clock
couples cell proliferation with mammalian daily physiology by rhythmically
pacing the key cell proliferation and tumor suppression pathways at the cellular
level. Since the molecular clockworks operate as interlocked feedback loops,
disruption of either a positive or a negative loop would disrupt the stability of
the molecular clock leading to loss of control in the circadian homeostasis of
cell cycle progression. 29,135,156,244,245 Indeed, deregulation of both positive
and negative loops of molecular clock frequently occurs in the same type of
tumor in humans. 65,75,76,79,84,92,94-96,104,246,247
4.1.2 Control of DNA damage response by the molecular clock
An average human body contains about 10 14 cells, each receiving tens of
thousands of DNA lesions every day. If not repaired, these lesions induce
harmful mutations that could affect the survival of cells or even an organ-
ism. 248 DNA damage activates genes encoding key enzymes in DNA repair
machinery and cell cycle checkpoints that pause cell cycle progression to
give the cell time to repair damaged DNA before continuing to divide. 249
When DNA damage exceeds the capacity of the cell to repair, efficient elim-
ination of damaged cells by apoptosis or necrosis plays a key role in
suppressing tumor development. 250
DNA damage response in mammals is controlled mainly by two master
kinases, ATM and ataxia-telangiectasia and Rad3-related (ATR). 251,252
ATM/ATR targets the protein kinases CHK1 and CHK2, which together