A transcriptional coactivator, steroid receptor coactivator-3, selectively augments steroid receptor transcriptional activity.
Estrogen receptors ERalpha and ERbeta are members of the family of nuclear hormone receptors and act as ligand-inducible transcriptional factors, which regulate the expression of target genes on binding to cognate response elements. We report here the characterization of steroid receptor coactivator-3 (SRC-3), a coactivator of nuclear receptor transcription that is a member of a family of steroid receptor coactivators that includes SRC-1 and transcription intermediate factor-2. SRC-3 enhanced ERalpha and progesterone receptor-stimulated gene transcription in a ligand-dependent manner, but stimulation of ERbeta-mediated transcription was not observed. Protein-protein interaction assays, including real-time interaction analyses with BIAcore, demonstrated that the affinity of the ERalpha interaction with SRC-3 was much higher than that observed for the ERbeta interaction with SRC-3. Mutational analysis suggests a potential interplay between the transactivation function-1 and -2 domains of ERalpha and SRC-3. Furthermore, an intrinsic transactivation function was observed in the C-terminal half of SRC-3. Finally, SRC-3 was differentially expressed in various tissues and, among several tumor cells examined, was most abundant in the nuclear fraction of MCF-7 breast cancer cells. Therefore, SRC-3, a third member of a family of steroid receptor coactivators, has a distinct tissue distribution and intriguing selectivity between ERalpha and ERbeta.
Suen
C S
CS
Women's Health Research Institute, Wyeth-Ayerst Research, Radnor, Pennsylvania 19087, USA.
Berrodin
T J
TJ
Mastroeni
R
R
Cheskis
B J
BJ
Lyttle
C R
CR
Frail
D E
DE
D000123:Acetyltransferases; D015374:Biosensing Techniques; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D047628:Estrogen Receptor alpha; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases; D006801:Humans; D056921:Nuclear Receptor Coactivator 3; D015513:Oncogene Proteins; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D014018:Tissue Distribution; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic
D018076:DNA, Complementary; D047628:Estrogen Receptor alpha; D015513:Oncogene Proteins; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D015534:Trans-Activators; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3