The roles of protein-protein interactions and protein methylation in transcriptional activation by nuclear receptors and their coactivators.
Hormone-activated nuclear receptors (NR) bind to the promoters of their target genes and recruit coactivator proteins to help activate transcription. The p160 coactivators bind directly to activated NRs and recruit secondary coactivators CBP/p300 with protein acetyltransferase activity and CARM1 with protein methyltransferase activity. To further investigate the components of the p160 coactivator complex and their mechanisms of action, we have used two guiding assumptions. First, the coactivators constitute a signal transduction pathway that convey the signal from DNA-bound NRs to the transcription machinery. Second, each coactivator has signal input and signal output domains that facilitate signal transduction. These assumptions were used to address the mechanism by which CARM1 and the N-terminal region of p160 coactivators transmit activating signals to the transcription machinery. The p160-binding activity of CARM1 is in the same centrally located structural domain as the methyltransferase activity; the p160-binding domain anchors CARM1 to the target gene promoter and thereby serves as its signal input domain. CARM1 has two signal output mechanisms: the protein methyltransferase activity, which methylates histones and other proteins in the transcription initiation complex; and a strong autonomous activation function in the C-terminal region. We identified a protein, CCCP, which binds to the C-terminal region of CARM1 and cooperates synergistically with CARM1 to enhance NR function. We also defined the N-terminal region of p160 coactivators as another signal output domain, which binds a novel coactivator called coiled-coil coactivator (CoCoA). CoCoA acts synergistically with p160 coactivators to enhance NR function.
Stallcup
Michael R
MR
Department of Pathology, University of Southern California, HMR 301, 2011 Zonal Avenue, Los Angeles, CA 90089-9092, USA. stallcup@usc.edu
Kim
Jeong Hoon
JH
Teyssier
Catherine
C
Lee
Young-Ho
YH
Ma
Han
H
Chen
Dagang
D
D000123:Acetyltransferases / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D008745:Methylation; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins; D011506:Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C491719:MYBBP1A protein, human; D009687:Nuclear Proteins; D029543:Nucleocytoplasmic Transport Proteins; D011506:Proteins; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D000123:Acetyltransferases; D051548:Histone Acetyltransferases