The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 236

The choice of cell types and in vitro cell culture conditions used in a study
may lead to different conclusions on the role of a gene in cell cycle control.
For example, under confluent culture condition, serum-shocked differenti-
ated skeletal muscle cells and hepatocytes from Bmal1 / mice show high
level expression of p21 WAF1/CIP1 , leading to the conclusion that loss of
Bmal1 decreases the rate of cell proliferation. 179 However, when a human
RNAi library targeting 8000 human genes was studied to identify modula-
tors of p53 function using the BJ-TERT-tsLT cells under subconfluent con-
dition, which were originally isolated from normal human diploid foreskin
fibroblasts, Bmal1 was identified as a novel positive regulator of the tumor
suppressor p53. Inhibition of Bmal1 expression in this system led to loss
of p53-mediated G1 cell cycle arrest at least in part due to an inability to
activate the p53 target p21 WAF1/CIP1 . 69
In summary, genetic studies using various circadian gene-mutant mouse
models strongly suggest that as found in human studies, both positive and
negative loops of the molecular clock function in tumor suppression in
rodents ( Table 9.2 ).
4. THE ROLE OF THE MAMMALIAN CIRCADIAN CLOCK
IN TUMOR SUPPRESSION
Cancer is a multifactorial disease in vivo . Its initiation and progression
need various manifestations of abnormal physiological conditions. As the
master regulator of mammalian physiology, the circadian clock acts at the
molecular, cellular, tissue/organ, and organismal levels to suppress tumor
development by maintaining homeostasis of physiology.
4.1. The role of peripheral clock in tumor suppression
In cells of peripheral tissues, the clock orchestrates diverse cellular functions
in a diurnal oscillating pattern via generation of a network of gene expression
at the transcriptional and posttranscriptional levels. 9,197-199 Disruption of the
circadian profiles of this gene expression network leads to loss of homeostasis
in cell/tissue function, a key mechanism in circadian dysfunction-induced
diseases. Recent studies have revealed that in both human and experimental
animal models, circadian disruption specially increases the risk of cancers in
the immune, digestive, and reproductive systems that need daily cell prolif-
eration to support their functions. These findings highlight the importance
of circadian control of cell cycle progression in both homeostasis of tissue
function and tumor suppression in vivo . In peripheral tissues, the molecular