Epithelial morphogenesis and intestinal cancer: new insights in signaling mechanisms.

In this review, the major signal transduction pathways that have been shown to play an important role in intestinal homeostasis are highlighted. Each of them, the Wnt, Notch, Hedgehog, and Bone Morphogenetic Protein, as well as growth-factor regulated Receptor Tyrosine Kinases are depicted with a special emphasis through their involvement in stem cell maintenance and their role in intestinal tumorigenesis. Finally, we discuss recent data on the final steps of tumor progression, notably the formation of distant metastases. This multistep process is highly complex and still far from being understood while being of major importance for the survival of patients with digestive cancer.

Generation and characterization of EphA1 receptor tyrosine kinase reporter knockout mice.

Eph receptor tyrosine kinases (RTKs) are a highly conserved family of signaling proteins with functions in cellular migration, adhesion, apoptosis, and proliferation during both adult and embryonic life. Here, we describe a knock-in mouse in which EphA1 expression is disrupted via the insertion of an internal ribosome entry site (IRES)-human placental alkaline phosphatase (ALPP) reporter cassette into exon II of the EphA1 gene. This was shown to successfully knockout expression of endogenous EphA1 and enforce expression of the ALPP reporter by the EphA1 promoter. Staining for the ALPP reporter protein demonstrated an epithelially restricted expression pattern in mouse tissues. In EphA1 null mice, two separate phenotypes were identified: abnormal tail development manifesting as a kinky tail was found in approximately 80% of homozygous adults. A second, distinct abnormality present in approximately 18% of females was characterized by imperforate uterovaginal development with hydrometrocolpos and caused by a resistance of cells to apoptosis during reproductive tract canalization. These results indicate a possible role for EphA1 in tissue patterning and hormone-induced apoptotic processes.

Inhibition of stress-inducible kinase pathways by tumorigenic mutant p53.

More than 50% of human cancers contain p53 gene mutations and as a result accumulate altered forms of the full-length p53 protein. Although certain tumor types expressing mutant p53 protein have a poor prognostic process, the precise role of mutant p53 protein in highly malignant tumor cells is not well defined. Some p53 mutants, but not wild-type p53, are shown here to interact with Daxx, a Fas-binding protein that activates stress-inducible kinase pathways. Interaction of Daxx with p53 is highly dependent upon the specific mutation of p53. Tumorigenic mutants of p53 bind to Daxx and inhibit Daxx-dependent activation of the apoptosis signal-regulating kinase 1 stress-inducible kinases and Jun NH(2)-terminal kinase. Mutant p53 forms complexes with Daxx in cells, and consequently, mutant p53 is able to rescue cells from Daxx-dependent inhibition of proliferation. Thus, the accumulation of mutant p53 in tumor cells may contribute to tumorigenesis by inhibiting stress-inducible kinase pathways.

Maxillary transverse discrepancies and potentially impacted maxillary canines in mixed-dentition patients.

OBJECTIVE: To investigate the correlation between maxillary transverse discrepancy and the occurrence of impacted canines in patients during the mixed-dentition stage. MATERIALS AND METHODS: Panoramic radiographs and dental casts were evaluated of randomly selected patients in the mixed dentition. The experimental group consisted of 84 orthodontic patients with a maxillary transverse discrepancy. The control group included 100 orthodontic patients without a maxillary transverse discrepancy. Intermolar widths of the experimental group were measured and recorded. The permanent canines of both groups were placed into a sector classification by using a panoramic radiograph. The experimental group was then analyzed to identify whether these patients had an impacted maxillary canine associated with the transverse discrepancy. The results were further evaluated based on type of impaction (unilateral or bilateral). RESULTS: Results of this study showed that patients with a transverse discrepancy are more likely to have an impacted canine than those patients without a transverse discrepancy, with the impaction more likely being unilateral. However, patients with a transverse discrepancy do not have a greater likelihood of having a bilateral impaction compared with patients without a transverse discrepancy. CONCLUSIONS: There appears to be an association between potentially impacted canines and transverse discrepancies. Identification can be made early based on proper panoramic evaluation and clinical detection. If a possibly impacted canine is detected early, appropriate treatment should be taken to minimize complications and avoid definitive impaction.

Expression analysis of the Epha1 receptor tyrosine kinase and its high-affinity ligands Efna1 and Efna3 during early mouse development.

Interaction of Eph receptor tyrosine kinases with their membrane bound ephrin ligands initiates bidirectional signaling events that regulate cell migratory and adhesive behavior. Whole-mount in situ hybridization revealed overlapping expression of the Epha1 receptor and its high-affinity ligands ephrin A1 (Efna1) and ephrin A3 (Efna3) in the primitive streak and the posterior paraxial mesoderm during early mouse development. These results show complex and dynamic expression for all three genes with expression domains that are successively complementary, overlapping, and divergent.

A novel p53-inducible apoptogenic gene, PRG3, encodes a homologue of the apoptosis-inducing factor (AIF).

The p53 tumor suppressor protein induces cell cycle arrest or apoptosis in response to cellular stresses. We have identified PRG3 (p53-responsive gene 3), which is induced specifically under p53-dependent apoptotic conditions in human colon cancer cells, and encodes a novel polypeptide of 373 amino acids with a predicted molecular mass of 40.5 kDa. PRG3 has significant homology to bacterial oxidoreductases and the apoptosis-inducing factor, AIF, and the gene was assigned to chromosome 10q21.3-q22.1. Expression of PRG3 was induced by the activation of endogenous p53 and it contains a p53-responsive element. Unlike AIF, PRG3 localizes in the cytoplasm and its ectopic expression induces apoptosis. An amino-terminal deletion mutant of PRG3 that lacks a putative oxidoreductase activity retains its apoptotic activity, suggesting that the oxidoreductase activity is dispensable for the apoptotic function of PRG3. The PRG3 gene is thus a novel p53 target gene in a p53-dependent apoptosis pathway.