GAC63, a GRIP1-dependent nuclear receptor coactivator.
Nuclear receptors (NRs) regulate target gene transcription through the recruitment of multiple coactivator complexes to the promoter regions of target genes. One important coactivator complex includes a p160 coactivator (GRIP1, SRC-1, or ACTR) and its downstream coactivators (e.g., p300, CARM1, CoCoA, and Fli-I), which contribute to transcriptional activation by protein acetylation, protein methylation, and protein-protein interactions. In this study, we identified a novel NR coactivator, GAC63, which binds to the N-terminal region of p160 coactivators as well as the ligand binding domains of some NRs. GAC63 enhanced transcriptional activation by NRs in a hormone-dependent and GRIP1-dependent manner in transient transfection assays and cooperated synergistically and selectively with other NR coactivators, including GRIP1 and CARM1, to enhance estrogen receptor function. Endogenous GAC63 was recruited to the estrogen-responsive pS2 gene promoter of MCF-7 cells in response to the hormone. Reduction of the endogenous GAC63 level by small interfering RNA inhibited transcriptional activation by the hormone-activated estrogen receptor. Thus, GAC63 is a physiologically relevant part of the p160 coactivator signaling pathway that mediates transcriptional activation by NRs.
Department of Pathology, HMR301, University of Southern California, 2011 Zonal Avenue, Los Angeles, California 90089-9092, USA.
Yong-Heng
YH
Chen
Jeong Hoon
JH
Kim
Michael R
MR
Stallcup
D000818:Animals; D004967:Estrogens / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D051958:Nuclear Receptor Coactivator 2; D053766:Presenilin-2; D011401:Promoter Regions, Genetic / Q000235:genetics; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D004967:Estrogens; C503320:GAC63 protein, mouse; D008565:Membrane Proteins; C498001:NCOA2 protein, human; C498002:Ncoa2 protein, mouse; D051958:Nuclear Receptor Coactivator 2; C508861:PSEN2 protein, human; D053766:Presenilin-2; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors