Figure 5

Interlocked molecular feedback loops of mammals. CLOCK/ BMAL1 heterodimer acts as the transcriptional activator (positive element) for Period (Per) and Cryptochrome (Cry) genes. The PER/CRY protein complex is phosphorylated in the cytoplasm by specific kinases, which then acts as inhibitor for their own transcription (negative element). In addition, these heterodimers activate Bmal1 transcription. CLK/BMAL1 transcription is inhibited by REV-ERBα, which in turn is regulated by CLK/BMAL1. Thus, CLK/BMAL1 heterodimer appears to be one of the key components of mammalian molecular clock, which connects the two loops. The Period1 gene product (PER1) is light-sensitive and appears to be important for the light entrainment of mammalian molecular clock.