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University of Queensland (L.J.B., M.D., G.E.O.M.) Centre for
Molecular and Cellular Biology Ritchie Research Laboratories
Brisbane, 4072, Queensland, Australia
Centre Nationale de la
Recherche Scientifique (V.L.) Institut Pasteur Oncologie
Moléculaire Lille-France
Rev-erbA
and RVR are orphan nuclear receptors
that function as dominant transcriptional silencers. Ligand-independent
repression of transcription by Rev-erbA and RVR is mediated by the
nuclear receptor corepressors, N-CoR and its variants RIP (RXR
interacting protein) 13a and RIP13
1. The physical association
between the corepressors and Rev-erbA and RVR is dependent on the
presence of a receptor interaction domain (RID) in the N-CoR family.
Our previous study demonstrated that the E region of RVR and
Rev-erbA is necessary and sufficient for the in vivo
interaction with the nuclear receptor corepressor, RIP131. The
present investigation demonstrates that two corepressor interaction
regions, CIR-1 and CIR-2, separated by 
150 amino acids in the E
region of RVR, are required for the interaction with N-CoR, RIP13a, and
RIP131. The D region is not required for the physical interaction.
In contrast, the D and E regions of Rev-erbA were necessary for the
interaction with the N-CoR and RIP13a-RIDs in vivo,
suggesting that RIP131 and N-CoR/RIP13a differentially interact with
Rev-erbA. Mutagenesis of CIR-1, a novel domain that is highly
conserved between RVR and Rev-erbA, demonstrated that the N-terminal
portion of helix 3 plays a key role and is absolutely necessary for the
interaction with RIP131, RIP13a, and N-CoR. The phenylalanine
residues, F402 and F441, in RVR and Rev-erbA, respectively, were
critical residues in supporting corepressor interaction. Cotransfection
studies demonstrated that repression of a physiological target, the
human Rev-erbA promoter, by RVR was significantly impaired by
mutation of CIR-1 or deletion of CIR-2. Furthermore, overexpression of
either the N-CoR/RIP13a or RIP131-RIDs alleviated RVR-mediated
repression of the Rev-erbA promoter, demonstrating that corepressor
binding mediates the repression of a native target gene by RVR. A
minimal region containing juxtapostioned CIR-1 and CIR-2 was sufficient
for corepressor binding and transcriptional repression. In conclusion,
our study has identified a new corepressor interaction region, CIR-1,
in the N terminus of helix 3 in the E region of RVR and Rev-erbA,
that is required for transcriptional silencing. Furthermore, we provide
evidence that CIR-1 and CIR-2 may form a single corepressor interaction
interface.
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