Biology Reference
In-Depth Information
g -radiation was studied, and the aging phenotypes displayed by
irradiated Clock m/m mice are also commonly observed in other irradiated
circadian gene-mutant mouse models, 29,124,128,129 arolefor Clock in tumor
suppression cannot be ruled out without examining the cancer risk of
Clock / and Clock / ; Npas2 / mice as well as irradiated Clock m/m mice
after 80 weeks of age. This is because aging is considered a primary risk factor
for cancer, 157 and the mammalian CLOCK may play a direct role in DNA
damage repair after g -radiation. 158 In addition, CLOCK and NPAS2 play
overlapping roles in the molecular clock. 159,160 Unlike Per2 m/m and Per2 /
mice that show a similar deregulated circadian phenotype, 123,124,155,161
Clock m/m and Clock / mice display different circadian behavioral phenotypes
and patterns of deregulation of gene expression in somatic cells. 162-165
Fourth, the observations of aggressive aging phenotypes and lack of
tumor incidence among Bmal1 -null mice are not sufficient to exclude a role
for Bmal1 in tumor suppression. When circadian gene-mutant mice are kept
in stable 24-h LD cycles, most spontaneous tumors are identified after
50 weeks of age, 29 which is an age most Bmal1 / mice would not live
to. 125 After being treated with a sublethal dose of g -radiation, although
the maximal life span of Bmal1 / mice was further decreased, about
6-7% of them developed malignant lymphomas before or at about 40 weeks
of age. This rate of tumor development in irradiated Bmal1 / mice is very
similar to the reported rate of tumor development among irradiated Per- and
Cry- mutant mice. 29,124,128 In addition, Bmal1 รพ / mice that have a similar
life span as Per- and Cry- mutants display the same rate of spontaneous and
radiation-induced tumor development in the same organ systems as Per-
and Cry- mutant mice. 29
Bmal1-null mice also display a delay in anagen progression and decreased
cell proliferation in secondary hair germ cells, which is coupled with
increased G1 cell cycle block as shown by decreased levels of RB phosphor-
ylation, increased expression of cyclin-dependent kinase inhibitors
p21 WAF1/CIP1 and p16 Ink4A , and accelerated epidermal aging. 166 In contrast,
mice lacking Bmal1 only in keratinocytes show constitutive elevation of cell
proliferation and intracellular redox levels as well as deregulated UVB-
induced DNA damage in the epidermis at linear growth age after wean. 22
However, in a different study, the same keratinocyte-specific Bmal1 /
mouse model was reported to display aging phenotypes in the skin starting
from 10 months of age, an age most Bmal1 -null mice could not survive to. 125
The decreased regeneration of keratinocyte-specific Bmal1 / hair germ
cells reported in this study cannot be rescued by overexpressing oncogenic
SOS, a Ras activator, 167 suggesting an early onset of replicative or cellular
Search WWH ::




Custom Search