ROLE OF b-CATENIN IN COLO-RECTAL TUMORS

Adherens junctions or zonula adherens are essential elements required for establishing cell-cell contacts and are important in the maintenence of the integrity of the epithelial layres. These junctions may also play a role in 'contact inhibition'. The catenins (a, b, g ) are cytoplasmic proteins that are ubiquitously expressed. These proteins associate with E-cadherin at cellular junctions. a-catenin was initially described as an E-cadherin associated protein. However, it was subsequently shown that this protein also binds P-cadherin and N-cadherin. b-catenin has been shown to bind E-cadherin, N-cadherin and to co-immunoprecipitate with the adenomatous polyposis coli (APC) tumor suppressor protein. b-catenin interacts with Tcf and Lef transcription factors and is an essential member of the Wingless-Wnt signal transduction pathway. g-catenin associates with N-cadherin and E-cadherin and is a major component of desmosomes. At these sites, this protein is complexed to desmoglein. Increased tyrosine phosphorylation can disrupt catenin-cadherin complexes and therefore can affect the cell-cell adhesion.

In the March issue of Science, Korinek et al, describe the cloning and characterization of Tcf-4, a member of the Tcf family that is expressed in the colonic epithelium. It was shown that hTcf-4 transactivates the transcription only when it is associated with the b-catenin. In the nuclei of the colonic carcinoma cells, the hTcf-4 was stably bound to the b-catenin and was constitutively active. Presence of APC protein, however, resulted in the dissociation of the b-catenin from the hTcf-4 and therefore led to the loss of its transcriptional activity. Since it is thought that the inactivation of the APC gene which acts as a tumor suppressor leads to colorectal neoplasia, the findings of the Korinek et al, suggest that b-catenin may be implicated in this process. In the same issue of Science, Sparks et al, reported that the there may be two pathways for the inactivation of the suppressive effects of the APC. This may occur by mutations in the APC protein itself or in the b-catenin. The cells of colorectal tumors were found to have mutations that led to singificant alterations of the phosphorylation sites of the b-catenin. These findings show that APC, b-catenin. and Tcf-4 are involved in the development of colorectal tumors.

FIGURE LEGENDS (from the top):

Figure 1. Western blot analysis of the a, b and g catenins
Figure 2. Human b catenin
Figure 3. Polyps in familial polyposis coli

REFERENCES:

Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW: Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC.Science 1997 Mar 21;275(5307):1787-1790

Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H: Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science 1997 Mar 21;275(5307):1784-1787

Catenin Gene Map Locus: 3p22-p21.