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ADA3-containing complexes associate with estrogen receptor alpha.

ABSTRACT: Transcriptional repression and activation by nuclear receptors (NRs) are brought about by coregulator complexes. These complexes modify the chromatin environment of target genes and affect the activity of the basal transcription machinery. We have previously implicated the yeast ADA3 protein in transcriptional activation by estrogen and retinoid X receptors in yeast and mammalian cells. Here we report the cloning of the mouse homolog of ADA3 and its characterization with respect to the estrogen receptor alpha (ERalpha) function. Mouse mADA3 is 23% identical and 47% similar to yeast yADA3, and mADA3 in contrast to yADA3 does not interact with NRs directly even though it contains two LxxLL NR boxes. However, the ADA3-containing TBP-free-TAF-containing complex (TFTC) can interact with ERalpha in a ligand-independent manner, indicating that other subunits of the complex are sufficient to mediate interaction with NRs.

SUBMITTER: Benecke A

PROVIDER: S-EPMC117179 | biostudies-literature | 2002 Jun

REPOSITORIES: biostudies-literature

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ADA3-containing complexes associate with estrogen receptor alpha.

Benecke Arndt A Gaudon Claudine C Garnier Jean-Marie JM vom Baur Elmar E Chambon Pierre P Losson Régine R

Nucleic acids research 20020601 11

Transcriptional repression and activation by nuclear receptors (NRs) are brought about by coregulator complexes. These complexes modify the chromatin environment of target genes and affect the activity of the basal transcription machinery. We have previously implicated the yeast ADA3 protein in transcriptional activation by estrogen and retinoid X receptors in yeast and mammalian cells. Here we report the cloning of the mouse homolog of ADA3 and its characterization with respect to the estrogen ...[more]

PMID: 12034840

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Project description:Breast cancer resistance to the antiestrogens tamoxifen (OHT) and fulvestrant is accompanied by alterations in both estrogen-dependent and estrogen-independent signaling pathways. Consequently, effective inhibition of both pathways may be necessary to block proliferation of antiestrogen-resistant breast cancer cells. In this study, we examined the effects of apigenin, a dietary plant flavonoid with potential anticancer properties, on estrogen-responsive, antiestrogen-sensitive MCF7 breast cancer cells and two MCF7 sublines with acquired resistance to either OHT or fulvestrant. We found that apigenin can function as both an estrogen and an antiestrogen in a dose-dependent manner. At low concentrations (1 mumol/L), apigenin stimulated MCF7 cell growth but had no effect on the antiestrogen-resistant MCF7 sublines. In contrast, at high concentrations (>10 mumol/L), the drug inhibited growth of MCF7 cells and the antiestrogen-resistant sublines, and the combination of apigenin with either OHT or fulvestrant showed synergistic, growth-inhibitory effects on both antiestrogen-sensitive and antiestrogen-resistant breast cancer cells. To further elucidate the molecular mechanism of apigenin as either an estrogen or an antiestrogen, effects of the drug on estrogen receptor-alpha (ERalpha); transactivation activity, mobility, stability, and ERalpha-coactivator interactions were investigated. Low-dose apigenin enhanced receptor transcriptional activity by promoting interaction between ERalpha and its coactivator amplified in breast cancer-1. However, higher doses (>10 mumol/L) of apigenin inhibited ERalpha mobility (as determined by fluorescence recovery after photobleaching assays), down-regulated ERalpha and amplified in breast cancer-1 expression levels, and inhibited multiple protein kinases, including p38, protein kinase A, mitogen-activated protein kinase, and AKT. Collectively, these results show that apigenin can function as both an antiestrogen and a protein kinase inhibitor with activity against breast cancer cells with acquired resistance to OHT or fulvestrant. We conclude that apigenin, through its ability to target both ERalpha-dependent and ERalpha-independent pathways, holds promise as a new therapeutic agent against antiestrogen-resistant breast cancer.

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ADA3-containing complexes associate with estrogen receptor alpha.

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ADA3-containing complexes associate with estrogen receptor alpha.

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