A Direct Interaction of Axonin-1 with NgCAM-related Cell Adhesion Molecule (NrCAM) Results in Guidance, but not Growth of Commissural Axons

An interaction of growth cone axonin-1 with the floor-plate NgCAM-related cell adhesion molecule (NrCAM) was shown to play a crucial role in commissural axon guidance across the midline of the spinal cord. We now provide evidence that axonin-1 mediates a guidance signal without promoting axon elongation. In an in vitro assay, commissural axons grew preferentially on stripes coated with a mixture of NrCAM and NgCAM. This preference was abolished in the presence of anti–axonin-1 antibodies without a decrease in neurite length. Consistent with these findings, commissural axons in vivo only fail to extend along the longitudinal axis when both NrCAM and NgCAM interactions, but not when axonin-1 and NrCAM or axonin-1 and NgCAM interactions, are perturbed. Thus, we conclude that axonin-1 is involved in guidance of commissural axons without promoting their growth

Cimetidine inhibits salivary gland tumor cell adhesion to neural cells and induces apoptosis by blocking NCAM expression

<p>Abstract</p> <p>Background</p> <p>Cimetidine, a histamine type-2 receptor antagonist, has been reported to inhibit the growth of glandular tumors such as colorectal cancer, however the mechanism of action underlying this effect is unknown. Adenoid cystic carcinoma is well known as a malignant salivary gland tumor which preferentially invades neural tissues. We demonstrated previously that human salivary gland tumor (HSG) cells spontaneously express neural cell adhesion molecule (NCAM), that HSG cell proliferation may be controlled via a homophilic (NCAM-NCAM) binding mechanism and that NCAM may be associated with perineural invasion by malignant salivary gland tumors. We further demonstrated that cimetidine inhibited NCAM expression and induced apoptosis in HSG cells. Here, we investigated the effects of cimetidine on growth and perineural/neural invasion of salivary gland tumor cells.</p> <p>Methods</p> <p>In this study, we have examined the effect of cimetidine on cancer cell adhesion to neural cells <it>in vitro</it>, one of the critical steps of cancer invasion and metastasis. We have also used an <it>in vivo </it>carcinogenesis model to confirm the effect of cimetidine.</p> <p>Results</p> <p>We have demonstrated for the first time that cimetidine can block the adhesion of HSG cells to neural cell monolayers and that it can also induce significant apoptosis in the tumor mass in a nude mouse model. We also demonstrated that these apoptotic effects of cimetidine might occur through down-regulation of the cell surface expression of NCAM on HSG cells. Cimetidine-mediated down-regulation of NCAM involved suppression of the nuclear translocation of NF-κB, a transcriptional activator of NCAM gene expression.</p> <p>Conclusion</p> <p>These findings suggest that growth and perineural/neural invasion of salivary gland tumors can be blocked by administration of cimetidine via induction of apoptosis and in which NCAM plays a role.</p

Regulating amyloid precursor protein synthesis through an internal ribosomal entry site

Expression of amyloid precursor protein (APP) is critical to the etiology of Alzheimer's disease (AD). Consequently, regulating APP expression is one approach to block disease progression. To this end, APP can be targeted at the levels of transcription, translation, and protein stability. Little is currently known about the translation of APP mRNA. Here, we report that endogenous APP mRNA is translated in neural cell lines via an internal ribosome entry site (IRES) located in the 5′-untranslated leader. The functional unit of the APP IRES is located within the 5′ 50 nucleotides of the 5′-leader. In addition, we found that the APP IRES is positively regulated by two conditions correlated with AD, increased intracellular iron concentration and ischemia. Interestingly, the enhancement of APP IRES activity is dependent upon de novo transcription. Taken together, our data suggest that internal initiation of translation of the APP mRNA is an important mode for synthesis of APP, a mechanism which is regulated by conditions that also contribute to AD

Axonin-1, Nr-CAM, and Ng-CAM play different roles in the in vivo guidance of chick commissural neurons

Immunoglobulin/fibronectin type III-like cell adhesion molecules have been implicated in axon pathfinding based on their expression pattern in the developing nervous system and on their complex interactions described in vitro. The present in vivo study demonstrates that interactions by two of these molecules, axonin-1 on commissural growth cones and Nr-CAM on floor plate cells, are required for accurate pathfinding at the midline. When axonin-1 or Nr-CAM interactions were perturbed, many commissural axons failed to cross the midline and turned instead along the ipsilateral floor plate border. In contrast, though perturbation of Ng-CAM produced a defasciculation of the commissural neurites, it did not affect their guidance across the floor plate