Target-specific utilization of transcriptional regulatory surfaces by the glucocorticoid receptor

被引:202
作者
Rogatsky, I
Wang, JC
Derynck, MK
Nonaka, DF
Khodabakhsh, DB
Haqq, CM
Darimont, BD
Garabedian, MJ
Yamamoto, KR
机构
[1] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA
[3] Univ Oregon, Inst Mol Biol, Eugene, OR 97403 USA
[4] NYU, Med Ctr, Dept Microbiol, New York, NY 10016 USA
关键词
D O I
10.1073/pnas.2336092100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The glucocorticoid receptor (GR) activates or represses transcription depending on the sequence and architecture of the glucocorticoid response elements in target genes and the availability and activity of interacting cofactors. Numerous GR cofactors have been identified, but they alone are insufficient to dictate the specificity of GR action. Furthermore, the role of different functional surfaces on the receptor itself in regulating its targets is unclear, due in part to the paucity of known target genes. Using DNA microarrays and real-time quantitative PCR, we identified genes transcriptionally activated by GR, in a translation-independent manner, in two human cell lines. We then assessed in U2OS osteosarcoma cells the consequences of individually disrupting three GR domains, the N-terminal activation function (AF) 1, the C-terminal AF2, or the dimer interface, on activation of these genes. We found that GR targets differed in their requirements for AF1 or AF2, and that the dimer interface was dispensable for activation of some genes in each class. Thus, in a single cell type, different GR surfaces were used in a gene-specific manner. These findings have strong implications for the nature of gene response element signaling, the composition and structure of regulatory complexes, and the mechanisms of context-specific transcriptional regulation.
引用
收藏
页码:13845 / 13850
页数:6
相关论文
共 53 条
[1]  
ADAMS M, 2003, IN PRESS MOL ENDOCRI
[2]   Quantitative analysis of mRNA amplification by in vitro transcription [J].
Baugh, L. R. ;
Hill, A. A. ;
Brown, E. L. ;
Hunter, Craig P. .
NUCLEIC ACIDS RESEARCH, 2001, 29 (05)
[3]   Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition [J].
Bledsoe, RK ;
Montana, VG ;
Stanley, TB ;
Delves, CJ ;
Apolito, CJ ;
McKee, DD ;
Consler, TG ;
Parks, DJ ;
Stewart, EL ;
Willson, TM ;
Lambert, MH ;
Moore, JT ;
Pearce, KH ;
Xu, HE .
CELL, 2002, 110 (01) :93-105
[4]   A METHOD FOR THE RAPID SEQUENCE-INDEPENDENT AMPLIFICATION OF MICRODISSECTED CHROMOSOMAL MATERIAL [J].
BOHLANDER, SK ;
ESPINOSA, R ;
LEBEAU, MM ;
ROWLEY, JD ;
DIAZ, MO .
GENOMICS, 1992, 13 (04) :1322-1324
[5]   TARGETED DISRUPTION OF THE GLUCOCORTICOID RECEPTOR GENE BLOCKS ADRENERGIC CHROMAFFIN CELL-DEVELOPMENT AND SEVERELY RETARDS LUNG MATURATION [J].
COLE, TJ ;
BLENDY, JA ;
MONAGHAN, AP ;
KRIEGLSTEIN, K ;
SCHMID, W ;
AGUZZI, A ;
FANTUZZI, G ;
HUMMLER, E ;
UNSICKER, K ;
SCHUTZ, G .
GENES & DEVELOPMENT, 1995, 9 (13) :1608-1621
[6]   A new dexamethasone-induced gene of the leucine zipper family protects T lymphocytes from TCR/CD3-activated cell death [J].
D'Adamio, F ;
Zollo, O ;
Moraca, R ;
Ayroldi, E ;
Bruscoli, S ;
Bartoli, A ;
Cannarile, L ;
Migliorati, G ;
Riccardi, C .
IMMUNITY, 1997, 7 (06) :803-812
[7]   DELINEATION OF A SMALL REGION WITHIN THE MAJOR TRANSACTIVATION DOMAIN OF THE HUMAN GLUCOCORTICOID RECEPTOR THAT MEDIATES TRANSACTIVATION OF GENE-EXPRESSION [J].
DAHLMANWRIGHT, K ;
ALMLOF, T ;
MCEWAN, IJ ;
GUSTAFSSON, JA ;
WRIGHT, APH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (05) :1619-1623
[8]   Structure and specificity of nuclear receptor-coactivator interactions [J].
Darimont, BD ;
Wagner, RL ;
Apriletti, JW ;
Stallcup, MR ;
Kushner, PJ ;
Baxter, JD ;
Fletterick, RJ ;
Yamamoto, KR .
GENES & DEVELOPMENT, 1998, 12 (21) :3343-3356
[9]   Cluster analysis and display of genome-wide expression patterns [J].
Eisen, MB ;
Spellman, PT ;
Brown, PO ;
Botstein, D .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (25) :14863-14868
[10]  
FOX MS, 2003, IN PRESS BIOL REPROD