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Nuclear Hormone Receptors for Heme: REV-ERB and REV-ERBβ Are Ligand-Regulated Components of the Mammalian Clock

Nuclear Receptor Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808

Address all correspondence and requests for reprints to: Dr. Thomas Burris, Nuclear Receptor Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808. E-mail: Thomas.burris{at}pbrc.edu.

The nuclear hormone receptors (NHRs), REV-ERB and REV-ERBβ, regulate a number of physiological functions including the circadian rhythm, lipid metabolism, and cellular differentiation. These two receptors lack the activation function-2 region that is associated with the ability of NHRs to recruit coactivators and activate target gene transcription. These NHRs have been characterized as constitutive repressors of transcription due to their lack of an identified ligand and their strong ability to recruit the corepressor, nuclear receptor corepressor. Recently, the porphyrin heme was demonstrated to function as a ligand for both REV-ERBs. Heme binds directly to the ligand-binding domain and regulates the ability of these NHRs to recruit nuclear receptor corepressor to target gene promoters. This review focuses on the physiological roles that these two receptors play and the implications of heme functioning as their ligand. The prospect that these NHRs, now known to be regulated by small molecule ligands, may be targets for development of drugs for treatment of diseases associated with aberrant circadian rhythms including metabolic and psychiatric disorders as well as cancer is also addressed.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARα  |  PPARγ  |  REV-ERBα  |  REV-ERBβ  |  Eip75  |  RORα

Coregulators:   PGC-1α  |  NCOR