Jörg Hülsken

β-Catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system

beta-Catenin is an essential component of the canonical Wnt signaling system that controls decisive steps in development. We employed here two conditional beta-catenin mutant alleles to alter beta-catenin signaling in the central nervous system of mice: one allele to ablate beta-catenin and the second allele to express a constitutively active beta-catenin. The tissue mass of the spinal cord and brain is reduced after ablation of beta-catenin, and the neuronal precursor population is not maintained. In contrast, the spinal cord and brain of mice that express activated beta-catenin is much enlarged in mass, and the neuronal precursor population is increased in size. beta-Catenin signals are thus essential for the maintenance of proliferation of neuronal progenitors, controlling the size of the progenitor pool, and impinging on the decision of neuronal progenitors to proliferate or to differentiate.

TUMOR-SUPPRESSOR GENE PRODUCTS IN CELL CONTACTS : THE CADHERIN-APC-ARMADILLO CONNECTION

Various structural components of intercellular junctions have recently been found to represent (or be related to) products of tumor-suppressor genes. The tumor-suppressor gene product adenomatous polyposis coli (APC) binds to beta 2-catenin (homologous to the product of Drosophila armadillo), which is cytoplasmically associated with the cell adhesion molecule E-cadherin.

Epithelial Differentiation and the Control of Metastasis in Carcinomas

Tumors of epithelial origin (carcinomas) are of major medical importance (DeVita et al. 1993). Multiple genetic changes in dominant and recessive oncogenes that contribute to carcinoma formation and progression have been identified. The most frequent mutations found in carcinomas include activating mutations in the ras family of genes, mutations that interfere with the function of p53, and amplification or overexpression of genes encoding tyrosine kinase receptors (Barbacid 1987; Aronson 1991; Hollstein et al. 1991; Vogelstein and Kinzler 1993; Hinds and Weinberg 1994). These mutations affect both the growth and the genetic stability of affected cells. A further critical step in the development of malignant carcinomas is their ability to invade the underlying tissue and to metastasize to distant sites. Early genetic approaches for the analysis of oncogenes have focused mainly on the induction of transformation, i.e., unregulated growth in fibroblasts, which has led in the past decade to a wealth of data on the pathways controlling normal and aberrant growth. In comparison, there has been a lag in understanding the molecular causes leading to the acquisition of the metastatic potential of carcinoma cells.

Reduced gene expression of E-cadherin and associated catenins in human cervical carcinoma cell lines

Cell-cell adhesion mediated by E-cadherin is often lost or disturbed in human carcinomas. For regular adhesive function, E-cadherin has to form complexes with peripheral cytoplasmic catenins which are multifunctional proteins that are also involved in signal transduction and growth regulation. We have analyzed the expression levels of the genes encoding alpha-catenin, beta-catenin and plakoglobin in correlation to the E-cadherin expression levels in cell lines derived from human cervical carcinomas. Reduced mRNA and protein levels were detected for plakoglobin, whereas alpha- and beta-catenin showed only reduced protein (but not mRNA) levels. The alterations in catenin gene expression were often associated with absent or reduced E-cadherin. The findings indicate that a reduction of catenin gene expression may contribute to the development of cervical carcinomas.