Ligand-dependent interaction between estrogen receptor alpha and adenomatous polyposis coli.
Numerous independent clinical and experimental studies indicate that estrogens confer a protective effect against development of intestinal tumors, however the molecular mechanisms involved remain unclear. Physiological effects of estrogens are predominantly mediated by the action of nuclear estrogen receptors (ERs). A multifunctional protein adenomatous polyposis coli (APC) is a tumor suppressor and thought to act as a gatekeeper in colon tumorigenesis, as loss of function APC mutations trigger the development of colorectal cancer. Here we report that APC physically associates with ERa in the ligand-dependent manner. We have shown in the endogenous setting that the ligand-activated ERa recruits APC to the promoters in ER target genes and that increased levels of ER-dependent recruitment of APC enhances the ER transactivation through stimulation of histone acetylation. Found in majority of human colon tumors APC truncation mutants lost the ability to interact with ER. Thus, here we present the first evidence of a functional interaction between APC and ER that may be accounted for a tumor protective action of estrogens.
Kouzmenko
Alexander P
AP
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Takeyama
Ken-ichi
K
Kawasaki
Yoshihiro
Y
Akiyama
Tetsu
T
Kato
Shigeaki
S
D011125:Adenomatous Polyposis Coli / Q000378:metabolism*; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000502:physiology; D017491:Genes, APC; D045325:HCT116 Cells; D006801:Humans; D008024:Ligands; D020218:Response Elements / Q000502:physiology; D017384:Sequence Deletion; D015533:Transcriptional Activation / Q000502:physiology
D025601:Adenomatous Polyposis Coli Protein; D047628:Estrogen Receptor alpha; D004967:Estrogens; D008024:Ligands