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g
-radiation was studied, and the aging phenotypes displayed by
irradiated
Clock
m/m
mice are also commonly observed in other irradiated
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
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
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
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-
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
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
The decreased regeneration of keratinocyte-specific
Bmal1
/
hair germ
cells reported in this study cannot be rescued by overexpressing oncogenic
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