Nucleic Acids Research, Vol 27, Issue 2 411-420, Copyright © 1999 by Oxford University Press
P Lau, P Bailey, DH Dowhan and GE Muscat
ROR/RZR is an orphan nuclear receptor that has no known ligand in the
'classical sense'. In the present study we demonstrate that RORalpha is
constitutively expressed during the differentiation of proliferating
myoblasts to post-mitotic multinucleated myotubes, that have acquired a
contractile phenotype. Exogenous expression of dominant negative
RORalpha1DeltaE mRNA in myogenic cells significantly reduces the endogenous
expression of RORalpha1 mRNA, represses the accumu-lation and delays the
activation of mRNAs encoding MyoD and myogenin [the muscle-specific basic
helix-loop-helix (bHLH) proteins] and p21(Waf- 1/Cip-1) (a cdk inhibitor).
Immunohistochemistry demonstrates that morpho-logical differentiation is
delayed in cells expressing the RORDeltaE transcript. Furthermore, the size
and development of mutlinucleated myotubes is impaired. The E region of
RORalpha1 interacts with p300, a cofactor that functions as a coactivator
in nuclear receptor and MyoD-mediated transactivation. Consistent with the
functional role of RORalpha1 in myogenesis, we observed that RORalpha1
directly interacts with the bHLH protein MyoD. This interaction was
mediated by the N-terminal activation domain of the bHLH protein, MyoD, and
the RORalpha1 DNA binding domain/C region. Furthermore, we demonstrated
that p300, RORalpha1 and MyoD interact in a non- competitive manner. In
conclusion, this study provides evidence for a biological role and positive
influence of RORalpha1 in the cascade of events involved in the activation
of myogenic-specific markers and cell cycle regulators and suggests that
crosstalk between theretinoid- relatedorphan (ROR) nuclear receptors and
the myogenic bHLH proteins has functional consequences for differentiation.
ARTICLES
Exogenous expression of a dominant negative RORalpha1 vector in muscle cells impairs differentiation: RORalpha1 directly interacts with p300 and myoD
University of Queensland, Centre for Molecular and Cellular Biology, Ritchie Research Laboratories, B402A, St Lucia, 4072, Queensland, Australia.
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