A nuclear factor, ASC-2, as a cancer-amplified transcriptional coactivator essential for ligand-dependent transactivation by nuclear receptors in vivo.
Many transcription coactivators interact with nuclear receptors in a ligand- and C-terminal transactivation function (AF2)-dependent manner. We isolated a nuclear factor (designated ASC-2) with such properties by using the ligand-binding domain of retinoid X receptor as a bait in a yeast two-hybrid screening. ASC-2 also interacted with other nuclear receptors, ... including retinoic acid receptor, thyroid hormone receptor, estrogen receptor alpha, and glucocorticoid receptor, basal factors TFIIA and TBP, and transcription integrators CBP/p300 and SRC-1. In transient cotransfections, ASC-2, either alone or in conjunction with CBP/p300 and SRC-1, stimulated ligand-dependent transactivation by wild type nuclear receptors but not mutant receptors lacking the AF2 domain. Consistent with an idea that ASC-2 is essential for the nuclear receptor function in vivo, microinjection of anti-ASC-2 antibody abrogated the ligand-dependent transactivation of retinoic acid receptor, and this repression was fully relieved by coinjection of ASC-2-expression vector. Surprisingly, ASC-2 was identical to a gene previously identified during a search for genes amplified and overexpressed in breast and other human cancers. From these results, we concluded that ASC-2 is a bona fide transcription coactivator molecule of nuclear receptors, and its altered expression may contribute to the development of cancers.
Mesh Terms:
Amino Acid Sequence, Animals, Cloning, Molecular, Gene Amplification, Gene Expression, Gene Expression Regulation, Neoplastic, Histone Acetyltransferases, Humans, Intracellular Signaling Peptides and Proteins, Ligands, Molecular Sequence Data, Neoplasms, Nuclear Proteins, Nuclear Receptor Coactivator 1, Nuclear Receptor Coactivators, Oocytes, Protein Binding, Receptors, Cytoplasmic and Nuclear, Recombinant Fusion Proteins, Sequence Alignment, Trans-Activators, Transcription Factors, Transcriptional Activation, Tumor Cells, Cultured, Two-Hybrid System Techniques, Xenopus
Amino Acid Sequence, Animals, Cloning, Molecular, Gene Amplification, Gene Expression, Gene Expression Regulation, Neoplastic, Histone Acetyltransferases, Humans, Intracellular Signaling Peptides and Proteins, Ligands, Molecular Sequence Data, Neoplasms, Nuclear Proteins, Nuclear Receptor Coactivator 1, Nuclear Receptor Coactivators, Oocytes, Protein Binding, Receptors, Cytoplasmic and Nuclear, Recombinant Fusion Proteins, Sequence Alignment, Trans-Activators, Transcription Factors, Transcriptional Activation, Tumor Cells, Cultured, Two-Hybrid System Techniques, Xenopus
J. Biol. Chem.
Date: Nov. 26, 1999
PubMed ID: 10567404
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