Jonathan C R Jones — Page 2

PubMed2002

beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium.

Tumor cells can evade chemotherapy by acquiring resistance to apoptosis. We investigated the molecular mechanism whereby malignant and nonmalignant mammary epithelial cells become insensitive to apoptosis. We show that regardless of growth status, formation of polarized, three-dimensional structures driven by basement membrane confers protection to apoptosis in both nonmalignant and malignant mammary epithelial cells. By contrast, irrespective of their malignant status, nonpolarized structures are sensitive to induction of apoptosis. Resistance to apoptosis requires ligation of beta4 integrins, which regulates tissue polarity, hemidesmosome formation, and NFkappaB activation. Expression of beta4 integrin that lacks the hemidesmosome targeting domain interferes with tissue polarity and NFkappaB activation and permits apoptosis. These results indicate that integrin-induced polarity may drive tumor cell resistance to apoptosis-inducing agents via effects on NFkappaB.

Apoptosis↗

PubMed2002

Function of laminins and laminin-binding integrins in gingival epithelial cell adhesion.

BACKGROUND: In human gingiva, epithelial cells attach to their adjacent tissues by means of specialized molecular adhesion complexes and a basement membrane. Little is known about the synthesis of adhesion proteins by gingival keratinocytes; we, therefore, studied how cultured immortalized gingival epithelial cells produce laminins and express laminin-binding integrins. We presumed that different laminins and integrins would be involved in the adhesion of gingival epithelial cells. METHODS: We cultured gingival keratinocytes and studied their production of laminins and expression of integrins using immunofluorescence microscopy, immunoprecipitation, and immunoblotting methods and by quantitative cell adhesion experiments. We also studied how gingival tissue expresses these adhesion proteins in vivo by using immunofluorescence microscopy. RESULTS: In immunofluorescence microscopy, the cells were seen to organize chains of laminin-5 (alpha3beta03gamma2) to extracellular patches, whereas the alpha5 chain of laminin-10 (alpha5betalgamma1) could only be seen intracellularly. Of the laminin-binding integrin subunits, integrin a6 subunit was organized to dotted arrays, typical of prehemidesmosomal adhesions, whereas integrin alpha3 subunit was located at cell-cell junctions, in prehemidesmosomal structures, and at some locations also in small focal-contact like patches. Integrin beta1 subunit was found at cell-cell junctions and in focal contacts. Immunoprecipitation experiments showed that the cells synthesize and secrete chains of laminin-5 and laminin-10. In quantitative cell adhesion experiments, the cells adhered efficiently to these laminins by using cooperatively integrin alpha3beta1 and alpha6beta1 integrin complexes. None of the other known laminin-binding integrin subunits appeared to be significantly involved in cell adhesion to these laminin isoforms. CONCLUSIONS: Our results provide new information on gingival epithelial cell adhesion and extracellular matrix production and may thus aid in the understanding of periodontal physiology.

Cell Adhesion↗