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University of Queensland (P.B., M.D., P.L., J.H., S.L.C.,
G.E.O.M.) Centre for Molecular and Cellular Biology
Ritchie Research Laboratories, B402A St Lucia, 4072 Queensland,
Australia
University of Southern California (Y.H., V.S.)
Institute of Genetic Medicine No. 140 Los Angeles, California
90033
Classical ligand-activated nuclear receptors
(e.g. thyroid hormone receptor, retinoic acid
receptor), orphan nuclear receptors (e.g.
Rev-erbA
/ß), Mad/Max bHLH (basic helix loop helix)-LZ proteins,
and oncoproteins, PLZF and LAZ3/BCL6, bind DNA and silence
transcription by recruiting a repressor complex that contains N-CoR
(nuclear receptor corepressor)/SMRT (silencing mediator of
retinoic acid and thyroid hormone receptor), Sin3A/B, and HDAc-1/-2
proteins. The function of the corepressor, N-CoR, in the process of
cellular differentiation and coupled phenotypic acquisition, has not
been investigated. We examined the functional role of N-CoR in
myogenesis (muscle differentiation), an ideal paradigm for the analysis
of the determinative events that govern the cell’s decision to divide
or differentiate. We observed that the mRNA encoding N-CoR was
suppressed as proliferating myoblasts exited the cell cycle, and formed
morphologically and biochemically differentiated myotubes. Exogenous
expression of N-CoR (but not RIP13) in myogenic cells ablated 1)
myogenic differentiation, 2) the expression of the myoD
gene family that encode the myogenic specific bHLH proteins, and 3) the
crucial cell cycle regulator, p21Waf-1/Cip-1
mRNA. Furthermore, N-CoR expression efficiently inhibits the
myoD-mediated myogenic conversion of pluripotential
C3H10T1/2 cells. We demonstrate that MyoD-mediated
transactivation and activity are repressed by N-CoR. The
mechanism involves direct interactions between MyoD and N-CoR;
moreover, the interaction was dependent on the amino-terminal
repression domain (RD1) of N-CoR and the bHLH region of MyoD.
Trichostatin A treatment significantly stimulated the activity of MyoD
by approximately 10-fold and inhibited the ability of N-CoR to repress
MyoD-mediated transactivation, consistent with the involvement of the
corepressor and the recruitment of a histone deacteylase activity in
the process. This work demonstrates that the corepressor N-CoR is a key
regulator of MyoD activity and mammalian differentiation, and that
N-CoR has a multifaceted role in myogenesis.
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