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with Multiple Steroid Receptors and Identification of an Internally Deleted ELE1ß Isoform
Division of Biochemistry (P.A., F.C., E.S., W.R., B.P.) and Laboratory for Experimental Medicine and Endocrinology (J.V.S., G.V.) Faculty of Medicine, Campus Gasthuisberg University of Leuven B-3000 Leuven, Belgium
Steroid-regulated gene transcription requires the
coordinate physical and functional interaction of hormone receptors,
basal transcription factors, and transcriptional coactivators. In this
context ARA70, previously called RFG and ELE1,
has been described as a putative coactivator that specifically enhances
the activity of the androgen receptor (AR) but not that of the
glucocorticoid receptor (GR), the progesterone receptor, or the
estrogen receptor (ER). Here we describe the cloning of the cDNA for
ELE1/ARA70 by RT-PCR from RNA derived from
different cell lines (HeLa, DU-145, and LNCaP). In accordance with the
previously described sequence, we obtained a 1845-bp PCR product for
the HeLa and the LNCaP RNA. Starting from T-47D RNA, however, an 860-bp
PCR product was obtained. This shorter variant results from an internal
985-bp deletion and is called ELE1ß; accordingly, the longer isoform
is referred to as ELE1
. The deduced amino acid sequence of ELE1,
but not that of ELE1ß, differs at specific positions from the one
previously published by others, suggesting that these two proteins are
encoded by different nonallelic genes. ELE1 is expressed in the
three prostate-derived cell lines examined (PC-3, DU-145, and LNCaP),
and this expression is not altered by androgen treatment. Of all rat
tissues examined, ELE1 expression is highest in the testis. This is
also the only tissue in which we could demonstrate ELE1ß expression.
Both ELE1 and ELE1ß interact in vitro with the AR, but
also with the GR and the ER, in a ligand-independent way.
Overexpression of either ELE1 isoform in DU-145, HeLa, or COS cells had
only minor effects on the transcriptional activity of the human AR.
ELE1 has no intrinsic transcription activation domain or histone
acetyltransferase activity, but it does interact with another
histone acetyltransferase, p/CAF, and the basal transcription factor
TFIIB. The interaction with the AR occurs through the ligand-binding
domain and involves the region corresponding to the predicted helix 3.
Mutation in this domain of leucine 712 to arginine greatly reduces the
affinity of the AR for ELE1 but has only moderate effects on its
transcriptional activity. Taken together, we have identified two
isoforms of the putative coactivator ARA70/ELE1
that may act as a bridging factor between steroid receptors and
components of the transcription initiation complex but which lack some
fundamental properties of a classic nuclear receptor coactivator.
Further experiments will be required to highlight the in
vivo role of ELE1 in nuclear receptor functioning.
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