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.
Lee
S K
SK
Center for Ligand and Transcription, Chonnam National University, Kwangju 500-757, Korea.
Anzick
S L
SL
Choi
J E
JE
Bubendorf
L
L
Guan
X Y
XY
Jung
Y K
YK
Kallioniemi
O P
OP
Kononen
J
J
Trent
J M
JM
Azorsa
D
D
Jhun
B H
BH
Cheong
J H
JH
Lee
Y C
YC
Meltzer
P S
PS
Lee
J W
JW
D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D005784:Gene Amplification; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1; D056918:Nuclear Receptor Coactivators; D009865:Oocytes / Q000378:metabolism; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics*; D014407:Tumor Cells, Cultured; D020798:Two-Hybrid System Techniques; D014981:Xenopus
D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; C486559:NCOA6 protein, human; D009687:Nuclear Proteins; D056918:Nuclear Receptor Coactivators; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1