Transcriptional activation and transformation by chimaeric Fos-estrogen receptor proteins: altered properties as a consequence of gene fusion.
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.
Institut für Molekularbiologie und Tumorforschung (IMT), Philipps-Universität Marburg, Germany.
M
M
Schuermann
G
G
Hennig
R
R
Müller
D016475:3T3 Cells; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic; D051379:Mice; D016760:Proto-Oncogene Proteins c-fos; D051381:Rats; D011960:Receptors, Estrogen / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection
D016760:Proto-Oncogene Proteins c-fos; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins