Ras-Mediated Deregulation of the Circadian Clock in Cancer

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Living systems possess an endogenous time-generating system –⁠ the circadian clock -⁠ accountable for a 24 hours oscillation in the expression of about 10% of all genes. In mammals, disruption of oscillations is associated to several diseases including cancer. In this manuscript, we address the following question: what are the elicitors of a disrupted clock in cancer? We applied a systems biology approach to correlate experimental, bioinformatics and modelling data and could thereby identify key genes which discriminate strong and weak oscillators among cancer cell lines. Most of the discriminative genes play important roles in cell cycle regulation, DNA repair, immune system and metabolism and are involved in oncogenic pathways such as the RAS/MAPK. To investigate the potential impact of the Ras oncogene in the circadian clock we generated experimental models harbouring conditionally active Ras oncogenes. We put forward a direct correlation between the perturbation of Ras oncogene and an effect in the expression of clock genes, found by means of mathematical simulations and validated experimentally. Our study shows that perturbations of a single oncogene are sufficient to deregulate the mammalian circadian clock and opens new ways in which the circadian clock can influence disease and possibly play a role in therapy.

Vyšlo v časopise: Ras-Mediated Deregulation of the Circadian Clock in Cancer. PLoS Genet 10(5): e32767. doi:10.1371/journal.pgen.1004338
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004338

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