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Intestinal cancer is one of the most common human cancers. Aberrant activation of the canonical Wnt signaling cascade, for example, caused by adenomatous polyposis coli (APC) gene mutations, leads to increased stabilization and accumulation of [beta]-catenin, resulting in initiation of intestinal carcinogenesis. The aryl hydrocarbon receptor (AhR) has dual roles in regulating intracellular protein levels both as a ligand-activated transcription factor and as a ligand-dependent E3 ubiquitin ligase. Here, we show that the AhR E3 ubiquitin ligase has a role in suppression of intestinal carcinogenesis by a previously undescribed ligand-dependent [beta]-catenin degradation pathway that is independent of and parallel to the APC system. This function of AhR is activated by both xenobiotics and natural AhR ligands, such as indole derivatives that are converted from dietary tryptophan and glucosinolates by intestinal microbes, and suppresses intestinal tumor development in Ap[c.sup.MinI+] mice. These findings suggest that chemoprevention with naturally-occurring and chemically-designed AhR ligands can be used to successfully prevent intestinal cancers. cecal cancer I ubiquitin ligase I [beta]-catenin I tumor chemoprevention

A loss-of-function mutation in the APC gene initiates colorectal carcinogenesis. Although the molecular mechanism of tumor initiation is complex, several modifier genes have been identified using mouse models, including the ApcMin mouse. Among the familial adenomatous polyposis mouse lines carrying a truncation mutation at codon 580 in Apc (Apc580D), one line (line 19-[Apc.sup.580D/+]) showed a remarkably reduced incidence of intestinal adenomas ( APC | modifier

Inhibitor of [beta]-catenin and T cell factor (ICAT) inhibits Wnt signaling by interfering with the interaction between [beta]-catenin and T cell factor. Here we show that [ICAT.sup.-/-] embryos exhibit malformation of the forebrain and craniofacial bones and lack the kidney. Analysis of the neuronal differentiation of embryonic stem cells revealed that Wnt3a redirects the fate of neural progenitors to a posterior character, whereas ICAT induces forebrain cells by inhibiting Wnt signaling. Furthermore, [ICAT.sup.-/-] embryonic stem cells were found to differentiate into neuronal cells possessing a posterior character. These results suggest that ICAT plays an important role in the anteriorization of neural cells by inhibiting the posteriorizing activity of Wnt signaling.

A novel beta-catenin-interacting protein, ICAT, has been identified. It has been found to inhibit interaction of beta-catenin with TCF-4 and represses beta-catenin-TCF-4-mediated transactivation. ICAT inhibits Xenopus axis formation in that it interferes with Wnt signaling. It appears likely that ICAT negatively regulates Wnt signaling by inhibition of the interaction of beta-catenin with TCF. It is also integral in development and cell proliferation.

Fyn, a member of the Src-family protein-tyrosine kinase (PTK), is implicated in learning and memory that involves N-methyl-D-aspartate (NMDA) receptor function. In this study, we examined how Fyn participates in synaptic plasticity by analyzing the physical and functional interaction between Fyn and NMDA receptors. Results showed that tyrosine phosphorylation of NR2A, one of the NMDA receptor subunits, was reduced in fyn-mutant mice. NR2A was tyrosine-phosphorylated in 293T cells when coexpressed with Fyn. Therefore, NR2A would be a substrate for Fyn in vivo. Results also showed that PSD-95, which directly binds to and coclusters with NMDA receptors, promotes Fyn-mediated tyrosine phosphorylation of NR2A. Different regions of PSD-95 associated with NR2A and Fyn, respectively, and so PSD-95 could mediate complex formation of Fyn with NR2A. PSD-95 also associated with other Src-family PTKs, Src, Yes, and Lyn. These results suggest that PSD-95 is critical for regulation of NMDA receptor activity by Fyn and other Src-family PTKs, serving as a molecular scaffold for anchoring these PTKs to NR2A.

The adenomatous polyposis coli gene (APC) is mutated in familial adenomatous polyposis and in sporadic colorectal tumors, and its product binds to the adherens junction protein β-catenin. Overexpression of APC blocks cell cycle progression. The APB-β-catenin complex was shown to bind to DLG, the human homolog of the Drosophila discs large tumor suppressor protein. This interaction required the carboxyl-terminal region of APC and the DLG homology repeat region of DLG. APC colocalized with DLG at the lateral cytoplasm in rat colon epithelial cells and at the synapse in cultured hippocampal neurons. These results suggest that the APC-DLG complex may participate in regulation of both cell cycle progression and neuronal function., The tumor suppressor gene APC is mutated in most cases of familial adenomatous polyposis (FAP), a dominantly inherited disease characterized by multiple adenomatous polyps in the colon (1, 2). The [...]

There appears to be a relationship between Wilms tumor protein (WT1) function and the regulation of cyclin/CDK complexes in which the cyclin/CDK inhibits WT1-induced cell cycle block. Experimental results show that microinjection of the WT1 gene blocks cell cycle progression from G1 to S phase and downregulates CDK-4 and CDK-2 kinase activities. The overexpression of cyclin/CDK results in abrogation of WT1 activity.

The adenomatous polyposis coli gene (APC) is mutated in familial adenomatous polyposis and in sporadic colorectal tumors. Here the APC gene product is shown to bind through its armadillo repeat domain to a Rac-specific guanine nucleotide exchange factor (GEF), termed Asef. Endogenous APC colocalized with Asef in mouse colon epithelial cells and neuronal cells. Furthermore, APC enhanced the GEF activity of Asef and stimulated Asef-mediated cell flattening, membrane ruffling, and lamellipodia formation in MDCK cells. These results suggest that the APC-Asef complex may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function., Mutations of the tumor suppressor gene APC are responsible for familial adenomatous polyposis, a dominantly inherited disease characterized by multiple adenomatous polyps in the colon (1). The APC gene is [...]

Wnt/Wingless directs many cell fates during development. Wnt/Wingless signaling increases the amount of Β-catenin/Armadillo, which in turn activates gene transcription. Here the Drosophila protein D-Axin was shown to interact with Armadillo and D-APC. Mutation of d-axin resulted in the accumulation of cytoplasmic Armadillo and one of the Wingless target gene products, Distalless. Ectopic expression of d-axin inhibited Wingless signaling. Hence, D-Axin negatively regulates Wingless signaling by down-regulating the level of Armadillo. These results establish the importance of the Axin family of proteins in Wnt/Wingless signaling in Drosophila., The Wnt/Wingless (Wg) signal-transduction pathway is involved in cell-cell signaling in many developmental processes (1). Wnt/Wg signaling promotes the stabilization of Β-catenin/Armadillo (Arm, a Drosophila homolog of Β-catenin) by negatively [...]

The Product of the Human c-erbB-2 Gene: A 185-Kilodalton Glycoprotein with Tyrosine Kinase Activity THE V-ERBB GENE IS AN ONCOGENE of avian erythroblastosis virus, which induces erythroblastosis and sarcomas in [...]