Fig. 1

CRY–Cop1 axis regulates circadian physiology at the posttranslational level in mammals. When nocturnal animals sleep during daytime, CRY levels are low in peripheral tissues such as liver, thus minimally inhibiting the Cop1 E3 ligase resulting in destabilization of Cop1 substrates such as c-Jun and other unknown substrates (indicated by “?”). CRY levels slowly increase and peak during night, which will maximally inhibit Cop1 activity during night. This will allow accumulation of Cop1 substrates. For Pck-1, a rate-limiting enzyme for gluconeogenesis, its transcription will be upregulated during daytime when GR and Glucagon signaling are not highly counteracted by inhibitors such as c-Jun and unknown substrate(s) of Cop1. In contrast, Pck-1 transcription is low during the night because these inhibitors accumulate at their peak levels