CIPC is a mammalian circadian clock protein without invertebrate homologues.
At the core of the mammalian circadian clock is a feedback loop in which the heterodimeric transcription factor CLOCK-Brain, Muscle Arnt-like-1 (BMAL1) drives expression of its negative regulators, periods (PERs) and cryptochromes (CRYs). Here, we provide evidence that CLOCK-Interacting Protein, Circadian (CIPC) is an additional negative-feedback regulator of the circadian clock. CIPC exhibits circadian regulation in multiple tissues, and it is a potent and specific inhibitor of CLOCK-BMAL1 activity that functions independently of CRYs. CIPC-CLOCK protein complexes are present in vivo, and depletion of endogenous CIPC shortens the circadian period length. CIPC is unrelated to known proteins and has no recognizable homologues outside vertebrates. Our results suggest that negative feedback in the mammalian circadian clock is divided into distinct pathways, and that the addition of new genes has contributed to the complexity of vertebrate clocks.
Zhao
Wen-Ning
WN
Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
Malinin
Nikolay
N
Yang
Fu-Chia
FC
Staknis
David
D
Gekakis
Nicholas
N
Maier
Bert
B
Reischl
Silke
S
Kramer
Achim
A
Weitz
Charles J
CJ
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001683:Biological Clocks / Q000502:physiology*; D056926:CLOCK Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D056931:Cryptochromes; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D047468:Immunoprecipitation; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008322:Mammals / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D011485:Protein Binding; D016372:RNA, Antisense / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection; D020798:Two-Hybrid System Techniques
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056931:Cryptochromes; D005420:Flavoproteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D056950:Period Circadian Proteins; D016372:RNA, Antisense; D015534:Trans-Activators; C538961:Bmal1 protein, mouse; C518934:CIPC protein, mouse; C539023:Per1 protein, mouse; C538944:Clock protein, mouse