Natural and synthetic retinoids are potent inhibitors of experimental carcinogenesis in animals and cause reversion of premalignant lesions in humans. In the model C3H 10T1/2 cell system, retinoids enhance postconfluent growth control, reversibly inhibit carcinogen-induced transformation, and enhance gap junctional intercellular communication. These effects are highly correlated. 10T1/2 cells were found to express low levels of connexin 43, a gap junctional protein first found in the heart. After treatment of confluent 10T1/2 cells with the synthetic retinoid tetrahydrotetramethylnapthalenylpropenylbenzoic acid (TTNPB), levels of connexin 43 mRNA and protein increased within 6 h of treatment, while elevation of junctional communication was detected within 12-18 h. The maximally effective concentration of TTNPB (10(-8) M) caused an approximate 10-fold elevation of connexin 43 gene transcripts after 72 h. Indirect immunofluorescence microscopy using a polyclonal antibody to the synthetic C-terminal region of connexin 43 demonstrated that TTNPB induced many fluorescent plaques in regions of cell-cell contact. These results provide a molecular basis for the retinoid-enhanced junctional communication in 10T1/2 cells. It is proposed that one action of retinoids is to modulate the intercellular transfer of signal molecules. These could mediate many of the physiological actions of retinoids on growth control and carcinogenesis.