RETINOIC ACID SUPPRESSES POLYOMA-VIRUS TRANSFORMATION BY INHIBITING TRANSCRIPTION OF THE C-FOS PROTOONCOGENE

In a previous paper, we predicted that retinoic acid suppressed polyom a virus transformation of rat F111 fibroblasts by affecting the expres sion of one or more genes that are involved in signalling pathways nor mally activated by the viral mT oncogene (Talmage and Lackey, Oncogene 7, 1837-1845, 1992). We had identified the cellular c-fos proto-oncog ene as a possible candidate target for both polyoma virus mT and retin oic acid regulated expression. In this report we present the results o f experiments that demonstrate that retinoic acid does indeed inhibit transcriptional transactivation of the c-fos promoter by polyoma virus , as well as by calf serum and purified serum growth factors. Further experiments demonstrate that inhibition of c-fos expression with antis ense fos RNA also prevents polyoma virus induced transformation. Resto ration of c-fos expression, even in the presence of retinoic acid, res tored transformation, indicating that retinoic acid inhibition of c-fo s expression is sufficient to explain the retinoid suppression of tran sformation. These results identify the c-fos protooncogene as a key nu clear target for mT-dependent transformation and show that the anticar cinogenic properties of retinoic acid can be brought about by inhibiti ng c-fos expression.