Adenomatous polyposis coli control of C-terminal binding protein-1 stability regulates expression of intestinal retinol dehydrogenases.
Mutations in the human adenomatous polyposis coli (APC) gene are thought to initiate colorectal tumorigenesis. The tumor suppressor function of APC is attributed primarily to its ability to regulate the WNT pathway by targeting the destruction of beta-catenin. We report here a novel role for APC in regulating degradation of the transcriptional co-repressor C-terminal-binding protein-1 (CtBP1) through a proteasome-dependent process. Further, CtBP1 suppresses the expression of intestinal retinol dehydrogenases, which are required for retinoic acid production and intestinal differentiation. In support of a role for CtBP1 in initiation of colorectal cancer, adenomas taken from individuals with familial adenomatous polyposis contain high levels of CtBP1 protein in comparison with matched, uninvolved tissue. The relationship between APC and CtBP1 is conserved between humans and zebrafish and provides a mechanistic model explaining APC control of intestinal retinoic acid biosynthesis.
Nadauld
Lincoln D
LD
Department of Oncological Sciences, University of Utah, Salt Lake City, Utah 84112, USA.
Phelps
Reid
R
Moore
Brent C
BC
Eisinger
Annie
A
Sandoval
Imelda T
IT
Chidester
Stephanie
S
Peterson
Peter W
PW
Manos
Elizabeth J
EJ
Sklow
Bradford
B
Burt
Randall W
RW
Jones
David A
DA
D000236:Adenoma / Q000235:genetics / Q000378:metabolism; D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017491:Genes, APC; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013045:Species Specificity; D014212:Tretinoin / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
C495270:CTNNB1 protein, human; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D051176:beta Catenin; D014212:Tretinoin; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; C022520:retinol dehydrogenase; D046988:Proteasome Endopeptidase Complex