Identification of c- MYC as a Target of the APC Pathway

Abstract

The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that is inactivated in most colorectal cancers. Mutations of APC cause aberrant accumulation of beta-catenin, which then binds T cell factor-4 (Tcf-4), causing increased transcriptional activation of unknown genes. Here, the c-MYC oncogene is identified as a target gene in this signaling pathway. Expression of c-MYC was shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c-MYC promoter. These results provide a molecular framework for understanding the previously enigmatic overexpression of c-MYC in colorectal cancers.

The Angiogenic Switch Molecule, Secreted FGF-Binding Protein, an Indicator of Early Stages of Pancreatic and Colorectal Adenocarcinoma

“…Carboxy-terminal truncations of the APC protein result in impairment of the ability of APC to interact with and downregulate betacatenin, a transcriptional activator regulated by the Wnt signaling pathway (7)(8)(9)(10)(11)(12)(13). The resulting constitutive overexpression of beta-catenin is likely responsible for the activation of growthpromoting oncogenes, such as cyclin D1 or c-myc (14)(15)(16). In 1990, Moser and colleagues identified an APC mutant mouse, namely Apc Min/+ , which carries a mutation in the APC gene similar to that detected in FAP and sporadic colorectal cancers (17).…”

Complex Expression Pattern of Wnt Ligands and Frizzled Receptors in Human Placenta and its Trophoblast Subtypes

“…Upon formation of a receptor complex containing Wnt, FZD and low-density lipoprotein receptor-related protein-5/6 (LRP-5/6) cytoplasmic β-catenin gets stabilised and is transferred to the nucleus where it interacts with transcription factors of the T cell-specific factor (TCF) family. Upon binding β-catenin converts TCFs into transcriptional activators inducing target genes for proliferation and invasion [4,5]. However, Wnts can also bind FZDs independently of LRP, activate or inhibit canonical Wnt signalling depending on the receptor context and induce non-canonical signal transduction pathways involving Ca 2+ as a second messenger [6][7][8].…”

Myc heterozygosity attenuates the phenotypes of APC deficiency in the small intestine

“…Mechanistically, this phenotype is associated with concurrent nuclear b-catenin and transcriptional activation of a large number of Wnt target genes. Of these target genes, the proto-oncogene Myc (He et al, 1998) appears to be of central importance, as co-deletion of both Apc and Myc within the murine intestinal epithelium rescues this 'crypt progenitor cell-like' phenotype. Concordantly, many of the Wnt targets deregulated after APC loss revert back to wild-type levels in double knockout APC Myc intestinal enterocytes (Ignatenko et al, 2006;Sansom et al, 2007).…”