Circadian regulation of c-MYC in mice.

Abstract

The circadian clock is a global regulatory mechanism that controls the expression of 50 to 80% of transcripts in mammals. Some of the genes controlled by the circadian clock are oncogenes or tumor suppressors. Among these <i>Myc</i> has been the focus of several studies which have investigated the effect of clock genes and proteins on <i>Myc</i> transcription and MYC protein stability. Other studies have focused on effects of <i>Myc</i> mutation or overproduction on the circadian clock in comparison to their effects on cell cycle progression and tumorigenesis. Here we have used mice with mutations in the essential clock genes <i>Bmal1</i>, <i>Cry1,</i> and <i>Cry2</i> to gain further insight into the effect of the circadian clock on this important oncogene/oncoprotein and tumorigenesis. We find that mutation of both <i>Cry1</i> and <i>Cry2</i>, which abolishes the negative arm of the clock transcription-translation feedback loop (TTFL), causes down-regulation of c-MYC, and mutation of <i>Bmal1,</i> which abolishes the positive arm of TTFL, causes up-regulation of the c-MYC protein level in mouse spleen. These findings must be taken into account in models of the clock disruption-cancer connection.