Regulated synthesis and functions of laminin 5 in polarized madin-darby canine kidney epithelial cells.

Renal tubular epithelial cells synthesize laminin (LN)5 during regeneration of the epithelium after ischemic injury. LN5 is a truncated laminin isoform of particular importance in the epidermis, but it is also constitutively expressed in a number of other epithelia. To investigate the role of LN5 in morphogenesis of a simple renal epithelium, we examined the synthesis and function of LN5 in the spreading, proliferation, wound-edge migration, and apical-basal polarization of Madin-Darby canine kidney (MDCK) cells.

Transcriptional profiles of intestinal tumors in Apc(Min) mice are unique from those of embryonic intestine and identify novel gene targets dysregulated in human colorectal tumors.

The adenomatous polyposis coli (APC) tumor suppressor is a major regulator of the Wnt signaling pathway in normal intestinal epithelium. APC, in conjunction with AXIN and GSK-3beta, forms a complex necessary for the degradation of beta-catenin, thereby preventing beta-catenin/T-cell factor interaction and alteration of growth-controlling genes such as c-MYC and cyclin D1. Inappropriate activation of the Wnt pathway, via Apc/APC mutation, leads to gastrointestinal tumor formation in both the mouse and human.

Enhanced tumor formation in mice heterozygous for Blm mutation.

Persons with the autosomal recessive disorder Bloom syndrome are predisposed to cancers of many types due to loss-of-function mutations in the BLM gene, which encodes a recQ-like helicase. Here we show that mice heterozygous for a targeted null mutation of Blm, the murine homolog of BLM, develop lymphoma earlier than wild-type littermates in response to challenge with murine leukemia virus and develop twice the number of intestinal tumors when crossed with mice carrying a mutation in the Apc tumor suppressor. These observations indicate that Blm is a modifier of tumor formation in the mouse and that Blm haploinsufficiency is associated with tumor predisposition, a finding with important implications for cancer risk in humans.

The APC tumor suppressor controls entry into S-phase through its ability to regulate the cyclin D/RB pathway.

Background & Aims: APC gene mutation is an early alteration in most colorectal tumors. In an attempt to determine its role in tumor development, we asked whether reintroducing wild-type APC into colorectal cancer cells with mutant APC affected cell cycle progression.

Methods: Using transient transfection, a plasmid containing the APC complementary DNA and DNA encoding the green fluorescent protein was expressed in SW480 cells.

Attenuated APC alleles produce functional protein from internal translation initiation.

Some truncating mutations of the APC tumor suppressor gene are associated with an attenuated phenotype of familial adenomatous polyposis coli (AAPC). This work demonstrates that APC alleles with 5' mutations produce APC protein that down-regulates beta-catenin, inhibits beta-catenin/T cell factor-mediated transactivation, and induces cell-cycle arrest. Transfection studies demonstrate that cap-independent translation is initiated internally at an AUG at codon 184 of APC.