Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 25, Pages 11614-11619Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1000438107
Keywords
ubiquitin; circadian rhythm
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Funding
- National Institutes of Health [DK45586, DK062434, DK077449]
- Penn Endocrinology and Diabetes Research Center [DK19525]
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The metazoan circadian clock mechanism involves cyclic transcriptional activation and repression by proteins whose degradation is highly regulated via the ubiquitin-proteasome pathway. The heme receptor Rev-erb alpha, a core negative component of the circadian network, controls circadian oscillation of several clock genes, including Bmal1 Rev-erb alpha protein degradation can be triggered by inhibitors of glycogen synthase kinase 3 beta, such as lithium, and also by serum shock, which synchronizes circadian rhythms in cultured cells. Here we report that two E3 ligases, Arf-bp1 and Pam (Myc-bp2), are copurified with Rev-erb alpha and required for its ubiquitination. RNA-interference-mediated depletion of Arf-bp1 and Pam stabilizes the Rev-erb alpha protein and protects Rev-erb alpha from degradation triggered by either lithium or serum shock treatment. This degradation pathway modulates the expression of Rev-erb alpha-regulated Clock gene and circadian function in mouse hepatoma cells. Thus, Arf-bp1 and Pam are novel regulators of circadian gene expression that target Rev-erb alpha for degradation.
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