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 theseMychas been the focus of several studies which have investigated the effect of clock genes and proteins onMyctranscription and MYC protein stability. Other studies have focused on effects ofMycmutation 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 genesBmal1,Cry1,andCry2to gain further insight into the effect of the circadian clock on this important oncogene/oncoprotein and tumorigenesis. We find that mutation of bothCry1andCry2, which abolishes the negative arm of the clock transcription–translation feedback loop (TTFL), causes down-regulation of c-MYC, and mutation ofBmal1,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.