SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins.
One component of the circadian clock in mammals is the Clock-Bmal1 heterodimeric transcription factor. Among its downstream targets, two genes, Cry1 and Cry2, encode inhibitors of the Clock-Bmal1 complex that establish a negative-feedback loop. We found that both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF(Fbxl3) ubiquitin ligase complex. This regulation by SCF(Fbxl3) is a prerequisite for the efficient and timely reactivation of Clock-Bmal1 and the consequent expression of Per1 and Per2, two regulators of the circadian clock that display tumor suppressor activity. Silencing of Fbxl3 produced no effect in Cry1-/-;Cry2-/- cells, which shows that Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins.
Busino
Luca
L
Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, MSB 599, New York, NY 10016, USA.
Bassermann
Florian
F
Maiolica
Alessio
A
Lee
Choogon
C
Nolan
Patrick M
PM
Godinho
Sofia I H
SI
Draetta
Giulio F
GF
Pagano
Michele
M
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000235:genetics; D056931:Cryptochromes; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018797:Cell Cycle Proteins; D056931:Cryptochromes; D044783:F-Box Proteins; D005420:Flavoproteins; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D044843:SKP Cullin F-Box Protein Ligases; D015534:Trans-Activators; D014157:Transcription Factors; D025801:Ubiquitin; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C538963:CRY1 protein, human; C538966:CRY2 protein, human; C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; C519795:FBXL3 protein, human; C519794:Fbxl3 protein, mouse; C539022:PER1 protein, human; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; C538943:CLOCK protein, human; C538944:Clock protein, mouse