The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 251

metabolism in a tissue and cell type-specific manner, leading to coupling of
peripheral

clock activity with tissue-specific functions in vivo

( Fig. 9.3 ) . 263,269,271,333,395-398
The initiation of G1 cell cycle progression in vivo is strictly controlled
by extracellular signals that activate proto-oncogenes c-Myc and/or E2f via
intracellular signaling including c-AMP-PKA, MAPK, Ras/ERK, JNK,
b -Catenin, and/or PI3K pathways in a cell type-specific manner. 173 Loss
of homeostasis in HPA axis and ANS signaling is frequently associated with
increased risk of cancer. 399,400 The role of the central clock in controlling
cell cycle progression in peripheral tissues can be explained by a model
obtained from studying circadian control of Myc transcriptional activation.
In cultured primary osteoblasts, isoproterenol-mediated ADR b signaling
stimulates cell cycle progression via a coupled activation of the peripheral
clock, the cell cycle clock, and p53 controlled by immediate early genes
including Per1 and Per2 , Ap1 and Myc , and ATM, respectively. Activation
of Myc leads to cell cycle progression, while activation of peripheral clock
prevents Myc overexpression and also stimulates ATM-mediated p53
induction. Loss of function in the Per genes, or elevated concentration
of isoproterenol, prevents the activation of peripheral clock and ATM
but not AP1-controlled Myc activation, leading to suppression of p53
induction and uncontrolled osteoblast proliferation due to Myc over-
expression. The PER proteins may be directly involved in SNS-stimulated
ATM activation since PER1 has been found to interact with ATM in
response to g -radiation, 82 whereas CRY proteins may prevent uncon-
trolled c-AMP-PKA-CREB-AP1- c-Myc signaling in response to ADR b
activation by directly inhibiting the G s alpha subunit (Gs a ) essential for
activating adenylate cyclase. 189

In vivo , Per- and Cry -mutant mice both
show uncontrolled SNS signaling and display a phenotype of neoplastic
growth of osteoblasts in bone. 29,149,150,189,190 Disruption of homeostasis
of SNS signaling by chronic jet lag is associated with the disruption of
peripheral clock function, suppression of p53 and Myc oncogenic activa-
tion, which is coupled with increased tumor development in all mouse
models studied. 29 Together with the previous reports on increased tumor
development and progression in rodent models treated with constant light
exposure, pinealectomy, chronic jet lag, or SCN lesion, these findings pro-
vide an explanation on how circadian dysfunction induces tumor develop-
ment in the absence of gene mutations, 117-122 which is especially relevant
for developing novel strategies for cancer prevention in the modern world
in which frequent disruption of endogenous circadian homeostasis due to