Hormone-conditional transformation by fusion proteins of c-Abl and its transforming variants.
Fusion of the hormone binding domain (HBD) of steroid receptors to transcription factors renders them hormone-dependent. We show here that an SH3-deleted, oncogenic variant of the Abl tyrosine kinase becomes hormone-dependent for transformation by fusion to the estrogen receptor (ER) HBD, extending the phenomenon to tyrosine kinases. Surprisingly, fusion of the HBD to the normal, non-transforming c-Abl (IV) protein activated transforming activity in a hormone-dependent fashion. In the presence of hormone, the c-Abl:ER fusion protein was transforming, cytoplasmic and tyrosine phosphorylated, whereas it was non-transforming, nuclear and hypophosphorylated without hormone. We have examined the kinetics of activation of the c-Abl:ER protein and found that protein synthesis is required both for kinase activation and for redistribution of the c-Abl:ER protein from the nucleus to the cytoplasm. We suggest that the activation of c-Abl could be due to HBD-mediated dimerization and/or to the ability to overexpress conditionally the normally toxic c-Abl protein. This novel approach may be applicable to a wide variety of proteins, particularly when activating mutations or physiological inducers are unknown or when the protein is toxic to cells.
Jackson
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Département de Biologie Cellulaire, Université de Genève, Sciences III, Switzerland.
Baltimore
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Picard
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D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic; D005455:Fluorescent Antibody Technique; D006728:Hormones / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D010766:Phosphorylation; D014176:Protein Biosynthesis; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D006728:Hormones; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D016315:Proto-Oncogene Proteins c-abl