The positive circadian regulators CLOCK and BMAL1 control G2/M cell cycle transition through Cyclin B1.
We previously identified a tight bidirectional phase coupling between the circadian clock and the cell cycle. To understand the role of the CLOCK/BMAL1 complex, representing the main positive regulator of the circadian oscillator, we knocked down Bmal1 or Clock in NIH3T33C mouse fibroblasts (carrying fluorescent reporters for clock and cell cycle phase) and analyzed timing of cell division in individual cells and cell populations. Inactivation of Bmal1 resulted in a loss of circadian rhythmicity and a lengthening of the cell cycle, originating from delayed G2/M transition. Subsequent molecular analysis revealed reduced levels of Cyclin B1, an important G2/M regulator, upon suppression of Bmal1 gene expression. In complete agreement with these experimental observations, simulation of Bmal1 knockdown in a computational model for coupled mammalian circadian clock and cell cycle oscillators (now incorporating Cyclin B1 induction by BMAL1) revealed a lengthening of the cell cycle. Similar data were obtained upon knockdown of Clock gene expression. In conclusion, the CLOCK/BMAL1 complex controls cell cycle progression at the level of G2/M transition through regulation of Cyclin B1 expression.
['Farshadi|Elham|E|', 'Yan|Jie|J|', 'Leclere|Pierre|P|', 'Goldbeter|Albert|A|', 'Chaves|Inês|I|', 'van der Horst|Gijsbertus T J|GTJ|']
D056930:ARNTL Transcription Factors D000818:Animals D056926:CLOCK Proteins D002940:Circadian Rhythm D056744:Cyclin B1 D059565:G2 Phase Cell Cycle Checkpoints D018507:Gene Expression Regulation, Developmental D006801:Humans D051379:Mice D041681:NIH 3T3 Cells
cell cycle Cyclin B1 Circadian clock CLOCK/BMAL1 G2/M transition