Receptor-selective coactivators as tools to define the biology of specific receptor-coactivator pairs.
In the absence of specific high-affinity agonists and antagonists, it has been difficult to define the target genes and biological responses attributable to many of the orphan nuclear receptors (ONRs). Indeed, it appears that many members of this receptor superfamily are not regulated by classical small molecules but rather their activity is controlled by interacting cofactors. Motivated by this finding, we have developed an approach to genetically isolate specific receptor-cofactor pairs in cells, allowing us to define the biological responses attributable to each complex. This is accomplished by using combinatorial peptide phage display to engineer the receptor interacting domain of each cofactor such that it interacts selectively with one nuclear receptor. In this study, we describe the customization of PGC-1alpha and its use to study the biology of the estrogen-related receptor alpha (ERRalpha) in cultured liver cells.
Gaillard
Stéphanie
S
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710.
Grasfeder
Linda L
LL
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710.
Haeffele
Christiane L
CL
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710.
Lobenhofer
Edward K
EK
Cogenics Division, Clinical Data, Inc., Research Triangle Park, North Carolina 27709.
Chu
Tzu-Ming
TM
SAS Institute, Inc., Cary, North Carolina 27513.
Wolfinger
Russ
R
SAS Institute, Inc., Cary, North Carolina 27513.
Kazmin
Dmitri
D
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710.
Koves
Timothy R
TR
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710; Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710; Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27710.
Muoio
Deborah M
DM
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710; Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710; Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27710.
Chang
Ching-Yi
CY
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710.
McDonnell
Donald P
DP
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710. Electronic address: donald.mcdonnell@duke.edu.
D045744:Cell Line, Tumor; D004798:Enzymes / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D010084:Oxidation-Reduction; D019151:Peptide Library; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000097983:ERRalpha Estrogen-Related Receptor
D004798:Enzymes; D005227:Fatty Acids; D006360:Heat-Shock Proteins; D019151:Peptide Library; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C486497:PPARGC1A protein, human