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Transcriptional Activity and MCF-7 Proliferation
Department of Molecular and Cellular Biology (I.T.R.C., R.M., D.M.L, B.W.O., C.L.S.), Baylor College of Medicine, Houston, Texas 77030-3498; and ISIS Pharmaceuticals (L.M.C., C.F.B.), Carlsbad, California 92008
Address all correspondence and requests for reprints to: Carolyn L. Smith, Ph.D., Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3498. E-mail: carolyns{at}bcm.tmc.edu
Steroid receptor RNA activator (SRA) is a novel coactivator for
steroid receptors that acts as an RNA molecule, whereas steroid
receptor coactivator (SRC) family members, such as steroid receptor
coactivator-1 (SRC-1) and transcriptional intermediary factor 2 (TIF2)
exert their biological effects as proteins. Individual overexpression
of each of these coactivators, which can form multimeric complexes
in vivo, results in stimulated ER
transcriptional
activity in transient transfection assays. However there is no
information on the consequences of reducing SRC-1, TIF2, or SRA
expression, singly or in combination, on ER transcriptional
activity. We therefore developed antisense oligodeoxynucleotides
(asODNs) to SRA, SRC-1, and TIF2 mRNAs, which
rapidly and specifically reduced the expression of each of these
coactivators. ER-dependent gene expression was reduced in a
dose-dependent fashion by up to 80% in cells transfected with these
oligonucleotides. Furthermore, treatment of cells with combinations of
SRA, SRC-1, and TIF2 asODNs reduced ER
transcriptional activity to an extent greater than individual
asODN treatment alone, suggesting that these
coactivators cooperate, in at least an additive fashion, to activate
ER-dependent target gene expression. Finally, treatment of MCF-7
cells with asODN against SRC-1 and TIF2 revealed a
requirement of these coactivators, but not SRA, for hormone-dependent
DNA synthesis and induction of estrogen-dependent pS2 gene expression,
indicating that SRA and SRC family coactivators can fulfill specific
functional roles. Taken together, we have developed a rapid method to
reduce endogenous coactivator expression that enables an assessment of
the in vivo role of specific coactivators on ER
biological action and avoids potential artifacts arising from
overexpression of coactivators in transient transfection assays.
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