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Blood, 1 December 2007, Vol. 110, No. 12, pp. 4047-4054.
Prepublished online as a Blood First Edition Paper on September 17, 2007; DOI 10.1182/blood-2007-05-088666.
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Submitted May 3, 2007
Accepted August 22, 2007
A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through upregulation of ubiquitin
Xinliang Mao, A Keith Stewart, Rose Hurren, Alessandro Datti, Xuegong Zhu, Yuanxiao Zhu, Changxin Shi, Kyle Lee, Rodger Tiedemann, Yanina Eberhard, Suzanne Trudel, Shengben Liang, Seth J. Corey, Lisa C. Gillis, Dwayne L. Barber, Jeffery L. Wrana, Shereen Ezzat, and Aaron D. Schimmer*
Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada
Mayo Clinic, Scottsdale, AZ, United States
Sinai-McLaughlin Assay and Robotic Technologies Facility, Mount Sinai Hospital, Toronto, Canada
The Department of Medicine, University of Toronto, Toronto, Canada
Pediatric Hematology and Oncology, MD Anderson Cancer Center, Houston, TX, United States
The Department of Medical Biophysics, University of Toronto, Toronto, Canada
The Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada
The McLaughlin Centre for Molecular Medicine, Toronto, Canada
* Corresponding author; email: aaron.schimmer{at}utoronto.ca.
The oncogene c-maf is frequently over-expressed in multiple myeloma cell lines and patient samples and contributes to increased cellular proliferation in part by inducing cyclin D2 expression. To identify regulators of c-maf, we developed a chemical screen in NIH3T3 cells stably over-expressing c-maf and the promoter of the c-maf target cyclin D2 driving luciferase. From a screen of 2400 off-patent drugs and chemicals, we identified glucocorticoids as c-maf dependent inhibitors of cyclin D2 transactivation. In multiple myeloma cell lines, glucocorticoids reduced levels of c-maf protein without influencing corresponding mRNA levels. Subsequent studies demonstrated that glucocorticoids increased ubiquitination-dependent degradation of c-maf and upregulated ubiquitin C mRNA. Moreover, ectopic expression of ubiquitin C recapitulated the effects of glucocorticoids, demonstrating regulation of c-maf protein through the abundance of the ubiquitin substrate. Thus, using a chemical biology approach, we identified a novel mechanism of action of glucocorticoids and a novel mechanism by which levels of c-maf protein are regulated by the abundance of the ubiquitin substrate.
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