The mechanism of Fos-induced transformation is still poorly understood. In the present study, we have asked whether genes whose products play a role in determining cell morphology might become deregulated in the course of Fos-induced transformation. A clear up-regulation in Fos-transformed rat fibroblasts was seen with ezrin, as well as tropomyosin (TM) -3 and -5B, while TM-1 was down-regulated. Significantly, the same genes were deregulated in a very similar, but hormone-inducible way in cells expressing a Fos-estrogen receptor fusion protein. In agreement with these results, Fos-expressing cells showed decreased levels of two TM isoforms of 36 and 38 kDa, and showed an impaired TM network. The significance of these observations is strengthened by the fact that the deregulation of TM expression has been shown to contribute to morphological transformation in other experimental systems. Deregulation of the TM and ezrin genes preceeds the induction of morphological transformation suggesting that this deregulation is not merely a consequence of transformation. On the other hand, deregulation follows the induction of direct Fos target genes. We therefore propose that a cascade of regulatory events is triggered by Fos oncoproteins which eventually leads to the deregulation of genes encoding cytoskeleton-associated proteins.