Figure 4.

Regulation of the clock by c-MYC and of c-MYC by the clock.A, c-MYC regulates Bmal1 by two mechanisms (55, 56, 57, 58). First, c-MYC, in the form of c-MYC-MAX-MIZ1 heterotrimer directly binds to the MIZ-binding site upstream of the Bmal1 promoter and directly inhibits its transcription. Second, in the form of c-MYC-MAX it binds to the E-boxes of the REV-ERB α/β genes (Nr1d1/2) and stimulates their transcription. NR1D1/2, in turn, binds to the RORE element of BMal1 and inhibits its transcription. B, regulation of c-MYC at the transcriptional level by the clock (59). The β-Catenin gene (Ctnnb1) contains an E-box in its 35th intron, to which BMAL1-CLOCK bind and act as a context-dependent repressor (23, 24, 59) to interfere with the transcription of Ctnnb1 (top). CRY-PER remove CLOCK-BMAL1 from the intron, activating Ctnnb1 transcription (bottom). β-catenin makes a complex with TCF/LEF, which stimulates c-Myc transcription. In CRY mutants, BMAL1-CLOCK remains bound to the E-box of Ctnnb1 intron and inhibits its transcription, and in the absence of, or with reduced levels of β-Catenin, c-Myc transcription is downregulated (top). C, regulation of MYC by the clock at a posttranscriptional level (60). When CRY2 is overexpressed by a strong promoter, such as the Igu promoter, it interacts with c-MYC and targets it for degradation by the ubiquitin/proteasome pathway, leading to reduced c-MYC levels.