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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. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-05-088666v1 110/12/4047    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mao, X. Articles by Schimmer, A. D. Search for Related Content PubMed PubMed Citation Articles by Mao, X. Articles by Schimmer, A. D. Related Collections Neoplasia Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin Xinliang Mao1,2, A. Keith Stewart1,3, Rose Hurren1, Alessandro Datti2,4, Xuegong Zhu1,5, Yuanxiao Zhu3, Changxin Shi3, Kyle Lee1, Rodger Tiedemann3, Yanina Eberhard1, Suzanne Trudel1,5,6, Shengben Liang1, Seth J. Corey7, Lisa C. Gillis1,6, Dwayne L. Barber1,6, Jeffery L. Wrana2,8,9, Shereen Ezzat1,5, and Aaron D. Schimmer1,2,5,6 1 Princess Margaret Hospital and the Ontario Cancer Institute, Toronto, ON; 2 McLaughlin Centre for Molecular Medicine, Toronto, ON; 3 Mayo Clinic, Scottsdale, AZ; 4 Sinai-McLaughlin Assay and Robotic Technologies Facility, Mount Sinai Hospital, Toronto, ON; 5 Department of Medicine, University of Toronto, Toronto, ON; 6 Department of Medical Biophysics, University of Toronto, Toronto, ON; 7 M. D. Anderson Cancer Center, Houston, TX; 8 Department of Medical Genetics and Microbiology, University of Toronto, Toronto, ON; and 9 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON The oncogene c-maf is frequently overexpressed 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 overexpressing c-maf and the cyclin D2 promoter 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 up-regulated 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Eberhard, S. P. McDermott, X. Wang, M. Gronda, A. Venugopal, T. E. Wood, R. Hurren, A. Datti, R. A. Batey, J. Wrana, et al. Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells Blood, October 1, 2009; 114(14): 3064 - 3073. [Abstract] [Full Text] [PDF] S. M. Corsello, G. Roti, K. N. Ross, K. T. Chow, I. Galinsky, D. J. DeAngelo, R. M. Stone, A. L. Kung, T. R. Golub, and K. Stegmaier Identification of AML1-ETO modulators by chemical genomics Blood, June 11, 2009; 113(24): 6193 - 6205. [Abstract] [Full Text] [PDF] R. E. Tiedemann, J. Schmidt, J. J. Keats, C.-X. Shi, Y. X. Zhu, S. E. Palmer, X. Mao, A. D. Schimmer, and A. K. Stewart Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-{kappa}B with antimyeloma activity in vitro and in vivo Blood, April 23, 2009; 113(17): 4027 - 4037. [Abstract] [Full Text] [PDF] X. Mao, S.-b. Liang, R. Hurren, M. Gronda, S. Chow, G. W. Xu, X. Wang, R. B. Zavareh, N. Jamal, H. Messner, et al. Cyproheptadine displays preclinical activity in myeloma and leukemia Blood, August 1, 2008; 112(3): 760 - 769. [Abstract] [Full Text] [PDF]

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