Fos proteins can act as negative regulators of cell growth independently of the fos transforming pathway.

The proto-oncogene c-fos is known to be an important positive regulator of cell growth and notably of the G0/G1 transition. However, we observed that v-fos or c-fos-transformed rat-1 fibroblasts paradoxically had a low growth rate as compared to control untransformed rat-1 cells. We determined that this slow growth mainly reflects an increase of the G1 phase of the cell cycle (up to fourfold). In addition, the G0 --> S progression of serum-starved fos-expressing rat-1 cells refed with serum was found to be also delayed as compared to rat-1 cells. The delayed G0 --> S progression in fos-expressing cells was accompanied by the inappropriate levels or kinetics of expression of several cell cycle-regulated genes (cyclin D1, cdc2, cdk2, cdk4 and rb). Furthermore, a clear uncoupling of the pRb hyperphosphorylation with the entry into S phase was found in these fos-expressing rat-1 cells. Interestingly, the effect of the Fos proteins on the cell cycle was independent of the fos transforming pathway, indicating that the effector genes for Fos proteins are likely to be different for each process. In conclusion, our results indicate that Fos proteins may act as negative regulators of cell growth in some cell types, independently of the fos transforming pathway.