Abstract
Protein zero (P(o)) is the immunoglobulin gene superfamily glycoprotein that mediates the self-adhesion of the Schwann cell plasma membrane that yields compact myelin. HeLa is a poorly differentiated carcinoma cell line that has lost characteristic morphological features of the cervical epithelium from which it originated. Normally, HeLa cells are not self-adherent. However, when P(o) is artificially expressed in this line, cells rapidly aggregate, and P(o) concentrates specifically at cell-cell contact sites. Rows of desmosomes are generated at these interfaces, the plasma membrane localization of cingulin and ZO-1, proteins that have been shown to be associated with tight junctions, is substantially increased, and cytokeratins coalesce into a cohesive intracellular network. Immunofluorescence patterns for the adherens junction proteins N-cadherin, alpha-catenin, and vinculin, and the desmosomal polypeptides desmoplakin, desmocollin, and desmoglein, are also markedly enhanced at the cell surface. Our data demonstrate that obligatory cell-cell adhesion, which in this case is initially brought about by the homophilic association of P(o) molecules across the intercellular cleft, triggers pronounced augmentation of the normally sluggish or sub-basal cell adhesion program in HeLa cells, culminating in suppression of the transformed state and reversion of the monolayer to an epithelioid phenotype. Furthermore, this response is apparently accompanied by an increase in mRNA and protein levels for desmoplakin and N-cadherin which are normally associated with epithelial junctions. Our conclusions are supported by analyses of ten proteins we examined immunochemically (P(o), cingulin, ZO-1, desmoplakin, desmoglein, desmocollin, N-cadherin, alpha-catenin, vinculin, and cytokeratin-18), and by quantitative polymerase chain reactions to measure relative amounts of desmoplakin and N-cadherin mRNAs. P(o) has no known signaling properties; the dramatic phenotypic changes we observed are highly likely to have developed in direct response to P(o)-induced cell adhesion. More generally, the ability of this "foreign" membrane adhesion protein to stimulate desmosome and adherens junction formation by augmenting well-studied cadherin-based adhesion mechanisms raises the possibility that perhaps any bona fide cell adhesion molecule, when functionally expressed, can engage common intracellular pathways and trigger reversion of a carcinoma to an epithelial-like phenotype.
Highlights
Protein zero (Po) has no known signaling properties; the dramatic phenotypic changes we observed are highly likely to have developed in direct response to Po-induced cell adhesion
We show that HeLa cells generate a complex response to Po-induced adhesion which greatly augments the placement of junctional proteins at cell-cell contacts, thereby compelling the assembly of certain junctional complexes, such as desmosomes and adherens junctions that are characteristic of normal epithelia
L-cell adhesion molecules (CAMs) apparently was capable of interacting with specific intracellular components of the $180 cells and it was concluded that cell-cell adhesion mediated by L-CAM directly brought about these cytoarchitectural changes
Summary
Po has no known signaling properties; the dramatic phenotypic changes we observed are highly likely to have developed in direct response to Po-induced cell adhesion. C ELL--cell contact in a forming epithelial monolayer is believed to be initiated by cell adhesion molecules (CAMs) 1that are Ca ++ dependent, as exemplified by E-cadherin (Gumbiner et al, 1988; Takeichi, 1991; Wollner et al, 1992). This contact is maintained and Address all correspondence to Drs D. From a therapeutic standpoint there is reason to believe that augmentation of functional Ca÷÷-dependent CAMs in carcinoma cells may be one key to reengaging the normal epithelial cell program through suppression of the transformed state
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