The Circadian Clock in Cancer Development and Therapy - Progress in Molecular Biology and Translational Science - page 232

Similarly, discrepancies in the effects of Per or Cry gene ablation on the
survival and tumor-developing rate of p53 -null mice can also be attributed
to a significant difference in the average and maximal life spans of p53 -null
mice, 29,127 which vary between 15-30 and 28-60 weeks of age, respec-
tively, as reported in different studies. 138-145 In accordance with our studies
demonstrating that chronic back-and-forth jet lag significantly accelerated
tumor development and reduced survival of p53- null mice, 29 mice harbor-
ing both a mutant p53 corresponding to the p53 R175H hotspot mutation in
humans and a mutant Per2 allele ( Per2 S662G ), 146 which leads to a short and
phase-advanced behavior rhythm among human patients suffering from
familial advanced sleep phase syndrome due to a single serine to glycine
mutation within the CKI e -binding region in PER2, 147 also display an
increased tumor incidence rate and decreased survival compared to
p53 R175H mice. 148 These findings suggest strongly that circadian dysfunction
cooperates with loss of p53 to promote tumor development.
Different research teams have also independently reached the same con-
clusion that Per- and Cry -mutant mice display a similar neoplastic growth of
osteoblasts in bone, 149,150 and that disruption of Period genes increases cancer
risk in mice. 29,124,148,151-153 Therefore, it would be important to verify the
role of Per and Cry genes in cancer risk since Per and Cry genes are both
indispensable for operating the same negative loop in the molecular clock
and display the same deregulated behavioral phenotypes. 123,154,155 In addi-
tion, despite of a high Per2 mRNA expression, PER2 protein is not detected
in peripheral tissues of Cry1 / ; Cry2 / mice. 156 Indeed, when Per- and
Cry- mutant mice of the same mouse strain were studied under exactly
the same conditions, the two mouse models displayed the same increased
rate of tumor development in the skeletal, immune, reproductive, and diges-
tive systems when kept in a steady-state 12-h light/12-h dark (24-h LD)
condition, in response to a sublethal dose of g -radiation, or treated with
chronic jet lag after g -radiation. 29 Together, the evidence obtained from
studying mice lacking Per or Cry under the same conditions strongly argues
that as found in human studies, the Cryptochrome genes also function in
tumor suppression in rodents.
Third, Clock m/m mice show a significant decrease in survival compared
to wild-type controls at 80 weeks of age after a sublethal dose of g -radiation.
No significant difference in tumor incidence or the rate of radiation-induced
apoptosis between wild-type and Clock m/m splenocytes was reported. The
decrease in the survival of irradiated Clock m/m mice was attributed to acceler-
ated aging but not tumor development. 129 Since only the apoptotic response
of Clock m/m splenocytes cultured in vitro toalethal,andnotasublethal,doseof