Several known inducers of the heat shock response (heat stress, arsenite, and heavy metals) were shown to cause a significant elevation of c-fos mRNA in HeLa cells. Heat stress resulted in a time-and temperaturedependent prolonged elevation in the level of c-fos mRNA, which was accompanied by increased translation of c-fos protein and its appearance in the nucleus. Elevated expression of c-fos during heat stress was paralleled by induction of hsp 70 mRNA, while levels of c-myc and metallothionein mRNAs declined. Treatment of HeLa cells with arsenite or heavy metals also resulted in increased levels of hsp 70, as well as c-fos mRNA. Although elevated expression of c-fos was prevented by inhibitors of RNA synthesis, analysis of relative rates of gene transcription showed that during heat stress there was a negligible change in c-fos transcription. Therefore, the enhanced expression of c-fos during the heat shock response is likely to occur primarily through posttranscriptional processes. Cycloheximide was also shown to significantly increase the c-fos mRNA level in HeLa cells. There results are consistent with the observation that these inducers of the heat shock response, as well as cycloheximide, repress protein synthesis and suggest that the increase in the level of c-fos mRNA is caused by an inhibition of protein synthesis. This supports the hypothesis that c-fos mRNA is preferentially stabilized under conditions which induce the heat shock response, perhaps by decreased synthesis of a short-lived protein which regulates c-fos mRNA turnover.The heat shock response is characterized by the rapid induction of a small set of proteins during heat stress or following exposure to stress-inducing agents such as arsenite or toxic levels of heavy metals (for reviews, see references 5, 7, and 16). The response is regulated at a number of levels. Heat shock genes are activated transcriptionally and their mRNAs are preferentially translated over non-heat-shock mRNAs. It is known that in Drosophila spp., genes normally expressed at 25°C, although active at 37°C, are blocked at the level of RNA processing and that proteins normally synthesized at 25°C are translated inefficiently if at all. Cells maintained at heat shock temperatures or released from exposure to stress-inducing agents gradually return to a more normal pattern of protein synthesis with increased translation of the pre-heat-shock mRNAs and reduced heat shock protein synthesis. It is believed that heat shock proteins function at normal temperatures in early development and during the cell cycle and that they function during stress to provide thermotolerance or to protect the cell from the effects of stress-inducing agents (5,7,16).Although the function of the proto-oncogene c-fos is unknown, it has been suggested that c-fos may be involved in cell differentiation (23,35) and in the process of cell division in response to growth factors (9). The c-fos protooncogene is expressed during prenatal cell growth, development, and differentiation, after partial hepatect...