TRANSCRIPTIONAL ACTIVATION AND TRANSFORMATION BY CHIMERIC FOS-ESTROGEN RECEPTOR PROTEINS - ALTERED PROPERTIES AS A CONSEQUENCE OF GENE FUSION

We have generated a series of conditionally active Fos and FosB protei ns by fusion with a C-terminal fragment of the human estrogen receptor (ER) which harbours the ligand binding site and the overlapping hormo ne-inducible transactivation domain TAF-2. The chimaeric Fos-ER protei ns showed estrogen-inducible activation of TRE (TPA-responsive element )-directed trapscription and hormone-dependent transformation of fibro blasts. These properties of the fusion proteins were independent of th e transregulatory and transforming properties of their normal non-fuse d 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, al though 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 a nd FosB-S-ER. The ER-fusion thus basically eliminated the differences in the transactivating potential seen among the various native Fos pro teins. Our data therefore provide evidence: (i) that the hormone bindi ng domain of the human estrogen receptor, apart from delivering hormon al control to a heterologous protein, can have profound effects on the activity of certain transcription factors, particularly on proteins w ith weak oncogenic and/or transregulatory potential, and (ii) that the transforming potential of c-Fos and FosB-S can be dramatically elevat ed by increasing their transactivating properties.