Insights into mechanisms of growth suppression by Cx26 in HeLa cells

Abstract

Expression of gap junction proteins (connexins) has long been documented to suppress the neoplastic phenotype in various tumors and transformed cells. However, the molecular basis of this response is not well understood. To this end, we examined the effect on growth suppression of HeLa cells expressing 3 different connexins. Of the three, only Cx26 clones showed markedly reduced growth in low serum and anchorage independent conditions. A mutant Cx26, which forms closed gap junctions, cannot mediate this effect. This result strongly suggests that the mechanism of growth suppression is mediated through the selective permeability of Cx26 gap junctions. Moreover, the presence of the Cx26 protein itself, even in the absence of coupling, is enough to bring partial arrest in G1. However, complete growth arrest in low serum requires this to be coupled to decreased viability of these partially arrested cells, and this appears to require functional gap junctions. We are currently seeking to identify the specific pathways regulating G1 checkpoints and cell survival that are selectively affected by Cx26 channels. Combined with parallel studies on the comparative permeabilities of gap junctions composed of different connexins, our studies should lead to the first picture of the molecular mechanisms that underlie growth suppression by gap junctions, since its original observation almost 4 decades ago.