The FBXL3 protein plays a role in the negative feedback loop of the mammalian molecular circadian rhythm. The PER and CRY proteins inhibit the transcription factors CLOCK and BMAL1. The degradation of PER and CRY prevent the inhibition of the CLOCK and BMAL1 protein heterodimer. In the nucleus, the FBXL3 protein targets CRY1 and CRY2 for polyubiquitination, which triggers the degradation of the proteins by the
proteasome. The FBXL3 protein is also involved in a related feedback loop that regulates the transcription of the
Bmal1 gene.
Bmal1 expression is regulated by the binding of
REV-ERBα and
RORα proteins to retinoic acid-related orphan receptor response elements (ROREs) in the
Bmal1 promoter region. The binding of the REV-ERBα protein to the promoter represses expression, while RORα binding activates expression. FBXL3 decreases the repression of
Bmal1 transcription by inactivating the REV-ERBα and
HDAC3 repressor complex. The FBXL3 protein has also been found to cooperatively degrade
c-MYC when bound to CRY2. The c-MYC protein is a
transcription factor important in regulating
cell proliferation. The CRY2 protein can function as a co-factor for the FBXL3 ligase complex and interacts with
phosphorylated c-MYC. This interaction promotes the ubiquitination and degradation of the c-MYC protein. == Interactions ==