Evidence for an overlapping role of CLOCK and NPAS2 transcription factors in liver circadian oscillators

被引:68
作者
Bertolucci, Cristiano [2 ]
Cavallari, Nicola [2 ]
Colognesi, Ilaria [2 ]
Aguzzi, Jacopo [3 ]
Chen, Zheng [4 ]
Caruso, Pierpaolo [1 ]
Foa, Augusto [2 ]
Tosini, Gianluca [3 ]
Bernardi, Francesco [1 ]
Pinotti, Mirko [1 ]
机构
[1] Univ Ferrara, Dipartimento Biochim & Biol Mol, I-44100 Ferrara, Italy
[2] Univ Ferrara, Dipartimento Biol & Evoluz, I-44100 Ferrara, Italy
[3] Morehouse Sch Med, Inst Neurosci, Circadian Rhythms & Sleep Disorders Program, Atlanta, GA 30310 USA
[4] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA
关键词
D O I
10.1128/MCB.01931-07
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The mechanisms underlying the circadian control of gene expression in peripheral tissues and influencing many biological pathways are poorly defined. Factor VII (FVII), the protease triggering blood coagulation, represents a valuable model to address this issue in liver since its plasma levels oscillate in a circadian manner and its promoter contains E-boxes, which are putative DNA-binding sites for CLOCK-BMAL1 and NPAS2-BMAL1 heterodimers and hallmarks of circadian regulation. The peaks of FVII mRNA levels in livers of wild-type mice preceded those in plasma, indicating a transcriptional regulation, and were abolished in Clock(-/-); Npas2(-/-) mice, thus demonstrating a role for CLOCK and NPAS2 circadian transcription factors. The investigation of Npas2(-/-) and Clock(Delta 19/Delta 19) mice, which express functionally defective heterodimers, revealed robust rhythms of FVII expression in both animal models, suggesting a redundant role for NPAS2 and CLOCK. The molecular bases of these observations were established through reporter gene assays. FVII transactivation activities of the NPAS2-BMAL1 and CLOCK-BMAL1 heterodimers were (i) comparable (a fourfold increase), (ii) dampened by the negative circadian regulators PER2 and CRY1, and (iii) abolished upon E-box mutagenesis. Our data provide the first evidence in peripheral oscillators for an overlapping role of CLOCK and NPAS2 in the regulation of circadianly controlled genes.
引用
收藏
页码:3070 / 3075
页数:6
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