Nucleic Acids Research, Vol 24, Issue 18 3481-3489, Copyright © 1996 by Oxford University Press
L Burke, M Downes, A Carozzi, V Giguere and GE Muscat
RVR/Rev-erb beta/BD73 is an orphan steroid receptor that has no known
ligand in the "classical' sense. RVR binds as a monomer to an element which
consists of an A/T-rich sequence upstream of the consensus hexameric
half-site. However, RVR does not activate transcription and blocks
transactivation of this element by ROR/RZR. The mechanism of RVR action
remains obscure, hence we used the GAL4 hybrid system to identify and
characterize an active transcriptional silencer in the ligand binding
domain (LBD) of RVR. Rigorous deletion and mutational analysis demonstrated
that this repressor domain is encoded by amino acids 416-449 of RVR.
Furthermore, we demonstrated that efficient repression is dependent on the
so-called LBD-specific signature motif, (F/W)AKxxxxFxxLxxxDQxxLL (which
spans loop3-4 and helix 4) and helix 5 (H5; identified in the crystal
structures of the steroid receptor LBDs). Although RVR is expressed in many
adult tissues, including skeletal muscle, and during embryogenesis, its
physiological function in differentiation and mammalian development remains
unknown. Since other 'orphans', e.g. COUP-TF II and Rev-erbA alpha, have
been demonstrated to regulate muscle and adipocyte differentiation, we
investigated the expression and functional role of RVR during mouse
myogenesis. In C2C12 myogenic cells, RVR mRNA was detected in proliferating
myoblasts and was suppressed when the cells were induced to differentiate
into post-mitotic, multinucleated myotubes by serum withdrawal. This
decrease in RVR mRNA correlated with the appearance of muscle-specific
markers (e.g. myogenin mRNA). RVR 'loss of function' studies by
constitutive over-expression of a dominant negative RVR delta E resulted in
increased levels of p21Cip1/Waf1 and myogenin mRNAs after serum withdrawal.
Time course studies indicated that expression of RVR delta E mRNA results
in the precocious induction and accumulation of myogenin and p21 mRNAs
after serum withdrawal. In addition, we demonstrated that over-expression
of the COUP-TF II and Rev-erbA alpha receptors in C2C12 cells completely
blocked induction of p21 mRNA after serum withdrawal. In conclusion, our
studies identified a potent transcriptional repression domain in RVR,
characterized critical amino acids within the silencing region and provide
evidence for the physiological role of RVR during myogenesis.
ARTICLES
Transcriptional repression by the orphan steroid receptor RVR/Rev-erb beta is dependent on the signature motif and helix 5 in the E region: functional evidence for a biological role of RVR in myogenesis
University of Queensland, Centre for Molecular and Cellular Biology, Ritchie Research Laboratories, St Lucia, Australia.
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