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E3 ligases Arf-bp1 and Pam mediate lithium-stimulated degradation of the circadian heme receptor Rev-erb alpha.


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 3beta, 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.

Pubmed ID: 20534529


  • Yin L
  • Joshi S
  • Wu N
  • Tong X
  • Lazar MA


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

June 22, 2010

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK062434
  • Agency: NIDDK NIH HHS, Id: DK077449
  • Agency: NIDDK NIH HHS, Id: DK19525
  • Agency: NIDDK NIH HHS, Id: DK45586

Mesh Terms

  • Amidine-Lyases
  • Animals
  • Cell Line
  • Chromatin Immunoprecipitation
  • Circadian Rhythm
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Lithium
  • Mice
  • Mixed Function Oxygenases
  • Multienzyme Complexes
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Ubiquitin-Protein Ligases