Transcriptional activation and transformation by chimaeric Fos-estrogen receptor proteins: altered properties as a consequence of gene fusion.

Abstract

We have generated a series of conditionally active Fos and FosB proteins by fusion with a C-terminal fragment of the human estrogen receptor (ER) which harbours the ligand binding site and the overlapping hormone-inducible transactivation domain TAF-2. The chimaeric Fos-ER proteins showed estrogen-inducible activation of TRE (TPA-responsive element)-directed transcription and hormone-dependent transformation of fibroblasts. These properties of the fusion proteins were independent of the transregulatory and transforming properties of their normal non-fused counterparts c-Fos, v-Fos, FosB-L and FosB-S. Thus c-Fos-ER and FosB-S-ER were strong transforming proteins in the presence of hormone, although c-Fos and FosB-S possess only marginal oncogenic properties. In addition, all fusion proteins showed increased transactivation in the presence of estrogen, again most noticeable in the case of c-Fos-ER and FosB-S-ER. The ER-fusion thus basically eliminated the differences in the transactivating potential seen among the various native Fos proteins. Our data therefore provide evidence: (i) that the hormone binding domain of the human estrogen receptor, apart from delivering hormonal control to a heterologous protein, can have profound effects on the activity of certain transcription factors, particularly on proteins with weak oncogenic and/or transregulatory potential, and (ii) that the transforming potential of c-Fos and FosB-S can be dramatically elevated by increasing their transactivating properties.