Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes.
Several lines of evidence indicate that the nuclear receptor corepressor (N-CoR) complex imposes ligand dependence on transcriptional activation by the retinoic acid receptor and mediates the inhibitory effects of estrogen receptor antagonists, such as tamoxifen, suppressing a constitutive N-terminal, Creb-binding protein/coactivator complex-dependent activation domain. Functional interactions between specific receptors and N-CoR or SMRT corepressor complexes are regulated, positively or negatively, by diverse signal transduction pathways. Decreased levels of N-CoR correlate with the acquisition of tamoxifen resistance in a mouse model system for human breast cancer. Our data suggest that N-CoR- and SMRT-containing complexes act as rate-limiting components in the actions of specific nuclear receptors, and that their actions are regulated by multiple signal transduction pathways.
Lavinsky
R M
RM
Howard Hughes Medical Institute, Department and School of Medicine, University of California at San Diego, La Jolla, CA 92093-0648, USA.
Jepsen
K
K
Heinzel
T
T
Torchia
J
J
Mullen
T M
TM
Schiff
R
R
Del-Rio
A L
AL
Ricote
M
M
Ngo
S
S
Gemsch
J
J
Hilsenbeck
S G
SG
Osborne
C K
CK
Glass
C K
CK
Rosenfeld
M G
MG
Rose
D W
DW
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004351:Drug Resistance; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D004965:Estrogen Antagonists; C539127:NCOR1 protein, human; C539130:NCOR2 protein, human; C539128:Ncor1 protein, mouse; C539131:Ncor2 protein, mouse; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D013629:Tamoxifen; D011494:Protein Kinases