Activities in Pit-1 determine whether receptor interacting protein 140 activates or inhibits Pit-1/nuclear receptor transcriptional synergy.
Pituitary-specific transcription of the evolutionarily related rat (r) GH and PRL genes involves synergistic interactions between Pit-1 and other promoter-binding factors including nuclear receptors. We show that Pit-1/thyroid hormone receptor (TR) and Pit-1/estrogen receptor (ER) synergistic activation of the rGH and rPRL promoters are globally similar. Both synergies depend upon the same activation functions in Pit-1 and also require activation function-2 conserved in TR and ER. The activation function-2 binding protein, RIP140, previously thought to be a nuclear receptor coactivator, strongly inhibits both Pit-1/TR and Pit-1/ER synergy. RIP140 inhibition is profoundly influenced, in a promoter-specific fashion, by a synergism-selective function in Pit-1: deletion of Pit-1 amino acids 72-100 switches RIP140 to an activator of Pit-1/ER and Pit-1/TR synergy at the rPRL promoter but not at the rGH promoter. Pit-1 amino acids 101-125 are required for RIP140 inhibition or activation again only at the rPRL promoter. Therefore, functions within one factor can determine the activity of a coactivator binding to its synergistic partner. This promoter context-specific synergistic interplay between transcription factors and coactivators is likely an essential determinant of cell-specific transcriptional regulation.
Chuang
F M
FM
Metabolic Research Unit, University of California, San Francisco 94143-0540, USA.
West
B L
BL
Baxter
J D
JD
Schaufele
F
F
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000078723:Nuclear Receptor Interacting Protein 1; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D011388:Prolactin / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D013234:Stem Cells / Q000378:metabolism; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D013006:Growth Hormone; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D011388:Prolactin; D011960:Receptors, Estrogen; D011988:Receptors, Thyroid Hormone; D011994:Recombinant Proteins; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; C494185:Pou1f1 protein, mouse; C494186:Pou1f1 protein, rat