Hormone-conditional transformation by fusion proteins of c-Abl and its transforming variants

Abstract

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.

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