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Two distinct nuclear receptor-interaction domains and CREB-binding protein-dependent transactivation function of activating signal cointegrator-2.

ASC-2 is a recently isolated transcriptional cointegrator molecule, which is amplified in human cancers and stimulates transactivation by nuclear receptors, AP-1, nuclear factor kappaB (NFkappaB), serum response factor (SRF), and numerous other transcription factors. ASC-2 contained two nuclear receptor-interaction domains, both of which are dependent on the integrity of their core LXXLL sequences. Surprisingly, the C-terminal LXXLL motif specifically interacted with oxysterol receptor LXRss, whereas the N-terminal motif bound a broad range of nuclear receptors. These interactions appeared to be essential because a specific subregion of ASC-2 including the N- or C-terminal LXXLL motif acted as a potent dominant negative mutant with transactivation by appropriate nuclear receptors. In addition, the autonomous transactivation domain (AD) of ASC-2 was found to consist of three separable subregions; i.e. AD1, AD2, and AD3. In particular, AD2 and AD3 were binding sites for CREB binding protein (CBP), and CBP-neutralizing E1A repressed the autonomous transactivation function of ASC-2. Furthermore, the receptor transactivation was not enhanced by ASC-2 in the presence of E1A and significantly impaired by overexpressed AD2. From these results, we concluded that ASC-2 directly binds to nuclear receptors and recruits CBP to mediate the nuclear receptor transactivation in vivo.

Pubmed ID: 11158331


  • Lee SK
  • Jung SY
  • Kim YS
  • Na SY
  • Lee YC
  • Lee JW


Molecular endocrinology (Baltimore, Md.)

Publication Data

February 22, 2001

Associated Grants


Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • CREB-Binding Protein
  • Cell Line
  • Escherichia coli
  • Gene Expression
  • Glutathione Transferase
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Nuclear Proteins
  • Nuclear Receptor Coactivators
  • Peptide Fragments
  • Plasmids
  • Polymerase Chain Reaction
  • Protein Structure, Secondary
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Receptors, Thyroid Hormone
  • Recombinant Fusion Proteins
  • Saccharomyces cerevisiae
  • Structure-Activity Relationship
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Activation
  • Transfection
  • beta-Galactosidase