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2016 ; 291
(20
): 10541-50
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Different Roles of Negative and Positive Components of the Circadian Clock in
Oncogene-induced Neoplastic Transformation
#MMPMID26961881
Katamune C
; Koyanagi S
; Shiromizu S
; Matsunaga N
; Shimba S
; Shibata S
; Ohdo S
J Biol Chem
2016[May]; 291
(20
): 10541-50
PMID26961881
show ga
In mammals, circadian rhythms in physiological function are generated by a
molecular oscillator driven by transcriptional-translational feedback loop
consisting of negative and positive regulators. Disruption of this circadian
clock machinery is thought to increase the risk of cancer development, but the
potential contributions of each component of circadian clock to oncogenesis have
been little explored. Here we reported that negative and positive transcriptional
regulators of circadian feedback loop had different roles in oncogene-induced
neoplastic transformation. Mouse embryonic fibroblasts prepared from animals
deficient in negative circadian clock regulators, Period2 (Per2) or
Cryptochrome1/2 (Cry1/2), were prone to transformation induced by co-expression
of H-ras(V12) and SV40 large T antigen (SV40LT). In contrast, mouse embryonic
fibroblasts prepared from mice deficient in positive circadian clock regulators,
Bmal1 or Clock, showed resistance to oncogene-induced transformation. In Per2
mutant and Cry1/2-null cells, the introduction of oncogenes induced expression of
ATF4, a potent repressor of cell senescence-associated proteins p16INK4a and
p19ARF. Elevated levels of ATF4 were sufficient to suppress expression of these
proteins and drive oncogenic transformation. Conversely, in Bmal1-null and Clock
mutant cells, the expression of ATF4 was not induced by oncogene introduction,
which allowed constitutive expression of p16INK4a and p19ARF triggering cellular
senescence. Although genetic ablation of either negative or positive
transcriptional regulators of the circadian clock leads to disrupted rhythms in
physiological functions, our findings define their different contributions to
neoplastic cellular transformation.