SIP Promotes Phosphorylation Of Mammalian Clock Proteins

SIP(Steriod receptor coactivator-interacting protein)is a novel ankyrin repeat containing protein.SIP gene encodes a member of the ankyrin repeat domains(KANK)family,which acts in cytoskeletal formation by modulating actin polymerization.The encoded protein plays a role in the chelating of the steroid receptor coactivators and other proteins.However,the role of the SIP protein in the circadian clock has not been reported to date.Estrogen receptor can phosphorylate SIP by CK2;Estrogen receptor ER [alpha] can promote the expression of PER2 to regulate the circadian clock.However,it is not clear what the function of SIP is in mammalian clock.This study found that SIP and estrogen inhibit the transcriptional activity of mammalian clock protein BMAL1 and CLOCK.The experimental results show that SIP not only interacts with BMAL1 and CLOCK but also promotes the phosphorylation and degradation of the BMAL1 protein.Estrogen not only directly phosphorylates BMAL1 but also promotes SIP phosphorylation of BMAL1.Immunoprecipitation experiments show that estrogen receptor ER ? can interact with BMAL1,CLOCK,SIP and CK2,and can promote the phosphorylation of BMAL1 through CK2.The effect of SIP on the transcriptional activity of BMAL1 and CLOCK is positively correlated with phosphorylation of BMAL1 and CLOCK.Moreover,SIP not only works in the main feedback loop,SIP promotes the transcriptional activity of ROR?.The specific role remains to be further studied.The results of these studies suggest that SIP and estrogen play a critical role in the mammalian circadian clock.