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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.

Pubmed ID: 10567404

Authors

  • Lee SK
  • Anzick SL
  • Choi JE
  • Bubendorf L
  • Guan XY
  • Jung YK
  • Kallioniemi OP
  • Kononen J
  • Trent JM
  • Azorsa D
  • Jhun BH
  • Cheong JH
  • Lee YC
  • Meltzer PS
  • Lee JW

Journal

The Journal of biological chemistry

Publication Data

November 26, 1999

Associated Grants

None

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