Adenomatous polyposis coli appears to regulate the degradation of Olaparib ��-catenin protein by recruiting ��-catenin into the negative regulatory complex for phosphorylation by glycogen synthase kinase 3�� (GSK3��) in the N-terminus (Dominguez et al, 1995; Yost et al, 1996; Korinek et al, 1997) and subsequent proteasomal degradation (Aberle et al, 1997). Intricate interactions among other ��-catenin binding partners also serve to facilitate the degradation of ��-catenin to maintain a delicate balance (Ikeda et al, 1998; Kishida et al, 1998; Li et al, 1999; Farr et al, 2000). In contrast to the proteasomal degradation of ��-catenin, which normally serves as a negative regulator of tumorigenesis, a positive regulator of ��-catenin and tumorigenesis has also been identified.

Protein kinase CK2 (formerly known as casein kinase 2), a serine/threonine kinase that is overexpressed in many malignancies, has been shown to phosphorylate ��-catenin in the midportion of the protein and enhance its stability (Song et al, 2000, 2003a). When ��-catenin escapes its negative regulatory mechanisms, it translocates into the nucleus and functions as a critical transcriptional coactivator of the T-cell factor/lymphocyte enhancer binding factor (TCF/LEF), which activates oncogenes, such as c-myc (He et al, 1998) and cyclin D1 (Shtutman et al, 1999). Thus, activating mutations or stabilisation of ��-catenin represent a critical process in the growth of the human CRC. Many ��-catenin target genes have also been demonstrated as important factors in the pathogenesis of CRC.

In particular, cyclin D1 was upregulated in human colorectal tumours and was associated with altered ��-catenin expression (Wang et al, 2002). Moreover, increased levels of both ��-catenin and cyclin D1 were found in a clinical analysis of tissue samples obtained from CRC patients (Utsunomiya et al, 2001) and in the colonic tissue extracts of mice when hyperproliferation/hyperplasia was induced (Sellin et al, 2001). Interestingly, an association between gastrin and ��-catenin was not made until Koh et al (2000) identified gastrin as a downstream target gene of ��-catenin/TCF transcription. Because these factors are important contributors to CRC growth, we sought to determine whether additional relationships might exist between gastrin and ��-catenin.

We have previously demonstrated the trophic properties of gastrin in mouse colorectal tumour cells (MC-26), in which the peptide caused a significant incorporation of [3H]thymidine at 24 and 48h (Yao et al, 2002). Furthermore, when MC-26 cells were injected subcutaneously into BALB/C mice and treated with amidated gastrin-17 (G-17) by continuous infusion, the weight and volume of resulting tumour Entinostat tissues were significantly greater than in untreated controls (Yao et al, 2002).