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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 ␤-catenin. We report here a novel role for APC in regulating degradation of the transcriptional co-repressor C-terminalbinding 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.Germline mutations in the adenomatous polyposis coli (APC) 2,3 tumor suppressor invariably result in familial adenomatous polyposis coli (FAP), a syndrome characterized by early onset colorectal cancer (1). The mechanism by which APC mutations cause colon tumorigenesis is attributed primarily to its role in negatively regulating canonical WNT signaling (2, 3). In this role, APC functions by targeting the transcriptional coactivator ␤-catenin for intracellular degradation through a proteasome-dependent pathway, thereby limiting its ability to associate with T cell factor/lymphoid enhancer factor nuclear transcription factors. Current evidence indicates that following APC mutation, ␤-catenin accumulates and translocates into the nucleus, where it partners with T cell factor/lymphoid enhancer factors to drive a program of cellular proliferation. As evidence for a genetic relationship between APC and WNT signaling, some studies cite the existence of rare, ␤-cateninactivating mutations in colon adenocarcinomas (4, 5). Importantly, however, these mutations do not appear to fully recapitulate the clinical phenotypes associated with APC mutation (6). This discrepancy raises the possibility of additional, ␤-cateninindependent functions for APC.A number of reports suggest that the functions of APC are not limited to its well established role in regulating canonical WNT signaling. For example, APC is reported to bind to microtubules, to regulate asymmetric cell division in Drosophila male germline stem cells, and to promote proper T-cell differentiation in mice (7-11). Further, we recently demonstrated that sporadic human colorectal carcinomas lack retinol dehydrogenases and that introduction of APC into human colon carcinoma cells lines induced the expression of the retinol dehydrogenase DHRS9 in a ␤-catenin-independent manner (12). In addition, apc mcr zebrafish lack expression of intestinal enzymes, such as rdh1l, that are required for retinoic acid production. Injection of apc mcr zebrafish embryos with mRNA encoding rdh1l or treatment with exogenous...