A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation 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, Aaron D. Schimmer

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4047-4054
Number of pages8
JournalBlood
Volume110
Issue number12
DOIs
StatePublished - Dec 1 2007

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Mao, X., Stewart, A. K., Hurren, R., Datti, A., Zhu, X., Zhu, Y., Shi, C., Lee, K., Tiedemann, R., Eberhard, Y., Trudel, S., Liang, S., Corey, S. J., Gillis, L. C., Barber, D. L., Wrana, J. L., Ezzat, S., & Schimmer, A. D. (2007). A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin. Blood, 110(12), 4047-4054. https://doi.org/10.1182/blood-2007-05-088666