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Cell Growth & Differentiation Vol. 10, 503-516, July 1999
© 1999 American Association for Cancer Research

The Zinc Finger Protein GLI Induces Cellular Sensitivity to the mTOR Inhibitor Rapamycin1

Iuri D. Louro, Peggy McKie-Bell, Helen Gosnell, Bianca C. Brindley, R. Patrick Bucy and J. Michael Ruppert2

Departments of Biochemistry and Molecular Genetics [I. D. L., H. G., J. M. R.] and Pathology [R. P. B.], Division of Hematology/Oncology, Department of Medicine, and the Comprehensive Cancer Center [P. M-B., J. M. R.], School of Medicine [B. C. B.], University of Alabama at Birmingham, Birmingham, Alabama 35294-3300

The protein synthetic machinery is activated by diverse genetic alterations during tumor progression in vivo and represents an attractive target for cancer therapy. We show that rapamycin inhibits the induction of transformed foci in vitro by GLI, a transcription factor that functions in the sonic hedgehog-patched pathway in tumors. In control cells, which were nontransformed epithelioid RK3E cells and derivative c-MYC- or RAS-transformed sister cell lines, rapamycin inhibits mTOR and mTOR-dependent activities but increases global protein synthesis, perhaps by activating a feedback mechanism. In GLI-transformed cells, rapamycin inhibits global protein synthesis and turnover and prevents cellular proliferation. In contrast to its effects on protein synthesis, rapamycin affects bromodeoxyuridine incorporation and cell cycle occupancy of GLI cells and control cells to a similar extent. Rare, variant GLI cells isolated by selection in rapamycin are also drug-resistant for protein metabolism and for cell cycle progression through G1. Our results indicate that sensitivity to rapamycin can be induced by a specific oncogene and that inhibition of global protein metabolism is linked to the rapamycin-sensitive phenotype.




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Molecular Cancer Research Cell Growth & Differentiation
Copyright © 1999 by the American Association of Cancer Research.