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Figure 3 | Molecular Cancer

Figure 3

From: Role of APC and DNA mismatch repair genes in the development of colorectal cancers

Figure 3

A model for the Wnt-signaling pathway. Panel A depicts the down-regulation of β-catenin transactivation activity in normal colonic epithelial cells. β-catenin remains in a complex of Axin/Axil/conductin, APC, GSK3β kinase and casein kinase 1 or 2 (CK1 or 2). In the absence of Wnt-signaling, GSK3β and CK1 or 2 kinases become active and phosphorylate β-catenin at serine and threonine residues in the N-terminal domain. Axin and APC promote phosphorylation of β-catenin by acting as a scaffoled protein and bringing together enzyme(s) and substrate(s). The phosphorylated β-catenin then binds with F-box protein β-TrCP of the Skp1-Cullin-F-box (SCF) complex of ubiquitin ligases and undergoes proteasomal degradation. Even though Tcf-Lef transcription factor without β-catenin may bind to DNA in the absence of β-catenin, the repressors and corepressors such as CtBP (carboxy-terminal binding protein), CBP (CREB-binding protein), Gro (Groucho), LRP (LDL-receptor-related protein) bind with Tcf-Lef and repress c-myc or cyclin D1 gene expression to control cell cycle progression. Some other known genes which are regulated by β-catenin/Tcf-Lef pathway are given here – cyclin D1, CDH1, Tcf-1, c-jun, Fra-1, PPARd, Gastrin, uPAR, MMP7, Conductin, CD44, Id2, Siamois, Xbra, Twin and Ubx. Panel B shows the role of mutations in the APC or β-catenin protein in the regulation of β-catenin level and its transactivation property in colon cancer cells. The mutant β-catenin escapes its degradation through Wnt-pathway and becomes stabilized in the cytoplasm. The stabilized level of β-catenin then heterodimerizes with Tcf-Lef transcription factor and locates into the nucleus, where it actively transcribes cell cycle related genes causing cellular proliferation. The binding of β-catenin with Tcf-Lef inhibits the binding of CtBP, CBP, Gro or LRP and potentiates its transcriptional activity.

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