ROLE OF CONNEXIN (GAP JUNCTION) GENES IN CELL-GROWTH CONTROL - APPROACH WITH SITE-DIRECTED MUTAGENESIS AND DOMINANT-NEGATIVE EFFECTS

Evidence is accumulating that connexin (Cx) genes form a family of tum or-suppressor genes. Our long-standing study revealed that, in almost all tumors, some abnormality in gap junction is observed, including lo ss or reduction of expression, aberrant localization of gap junction. In this study, we have examined the dominant-negative effects of mutan t (prepared by site-directed mutagenesis) Cx43 constructs in C6 glioma cells, and of mutant Cx26 constructs in HeLa cells, on tumorigenicity . The mutant Cx43 A253V (Ala 253 to Val) inhibited the tumor-suppressi ve function exerted by wild-type Cx43 in C6 cells. Similarly, the muta nt Cx26 P87L (Pro 87 to Leu) manifested dominant-negative inhibition o f connexin-mediated cell growth control in HeLa cells. These results s uggest that mutations of connexin genes can affect the tumor-suppressi ve function of gap junction and that gap junctional intercellular comm unication can be regulated by not only non-genotoxic hut also genotoxi c activities of environmental carcinogens. (C) 1998 Elsevier Science I reland Ltd. All rights reserved.