6. Effect of Erk vs. PI3 Kinase Activation by the Middle Tumour Antigen of Polyoma Virus Upon Gap Junctional, Intercellular Communication of Cultured Cells

Abstract

Gap junctions are protein channels that permit the passage of small molecules and ions between adjacent cells. Gap junctional permeability is thought to lead to decreased cellular proliferation. In fact, a number of oncogenes, such as the middle tumour antigen of polyoma virus (mT), are known to interrupt gap junctional, intercellular communication (GJIC). The Ras/Raf/Mek/Erk and phosphoinositide 3‐kinase (PI3 kinase)/Akt signalling pathways, two commonly studied pathways in malignancy, are both activated by mT, and are both required for complete transformation by mT. This study is the first to investigate the effects of Erk vs. PI3 kinase activation by mT on GJIC in cultured cells. To this effect, two mT mutants,impaired in their ability to activate either the Erk or PI3 kinase pathway, were expressed through retroviral infection in rat liver epithelial T51B cells which have extensive GJIC. A novel in situ electroporation technique was used to quantitate the degree of GJIC in T51B cells expressing each mT mutant. The results showed that the Erk‐activating mutant exhibited the interrupted GJIC that is characteristic of mT expression, while the PI3 kinase‐activating mutant displayed levels of GJIC comparable to those observed in wild‐type T51B cells. This suggests that Erk activation by mT is sufficient to suppress GJIC, while PI3 kinase activation, despite its contribution to neoplastic transformation, is unable to interrupt GJIC. Given the importance of GJIC in cellular proliferation, apoptosis and differentiation, identifying the pathways affecting gap junctional permeability may yield novel targets for cancer therapy.