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Disruption of the circadian clock due to the Clock mutation has discrete effects on aging and carcinogenesis

Marina P. Antoch, Victoria Y. Gorbacheva, Olena Vykhovanets, Illia A. Toshkov, Roman V. Kondratov, Anna A. Kondratova, Choogon Lee and Alexander Yu Nikitin

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The mammalian circadian system has been implicated in the regulation of various biological processes including those involved in genotoxic stress responses and tumor suppression. Here we report that mice with the functional deficiency in circadian transcription factor CLOCK (Clock/Clock mutant mice) do not display predisposition to tumor formation both during their normal lifespan or when challenged by γ-radiation. This phenotype is consistent with high apoptotic and low proliferation rate in lymphoid tissues of Clock mutant mice and is supported by the gene expression profiling of a number of apoptosis and cell cycle-related genes, as well as by growth inhibition of cells with CLOCK downregulation. At the same time, Clock mutant mice respond to low-dose irradiation by accelerating their aging program, and develop phenotypes that are reminiscent of those in Bmal1-deficient mice. Taken together, our results demonstrate the dichotomy in biological consequences of the disruption of the circadian clock with respect to ageing and cancer. They also highlight the existence of a complex interconnection between ageing, carcinogenesis and individual components of the circadian clock machinery.

Authors

Marina P. Antoch

Roswell Park Cancer Institute; Buffalo, NY

Victoria Y. Gorbacheva

Cleveland Clinic Foundation; Cleveland, OH

Olena Vykhovanets

Cleveland Clinic Foundation; Cleveland, OH

Illia A. Toshkov

Cornell University; Ithaca, NY

Roman V. Kondratov

Cleveland State University; Cleveland, OH

Anna A. Kondratova

Cleveland Clinic Foundation; Cleveland, OH

Choogon Lee

Florida State University; Tallahassee, FL

Alexander Yu Nikitin

Cornell University; Ithaca, NY

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.