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Degrasyn Activates Proteasomal-Dependent Degradation of c-Myc

Departments of ¹ Experimental Therapeutics and ² Experimental Diagnostic Imaging, University of Texas M. D. Anderson Cancer Center, Houston, Texas and ³ Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan

Requests for reprints: Nicholas J. Donato, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Room CCGC 4306, 1500 East Medical Center Drive, Ann Arbor, MI 48109. Phone: 734-615-5542; Fax: 734-647-9654; E-mail: ndonato{at}med.umich.edu.

c-Myc is a highly unstable transcription factor whose deregulation and increased expression are associated with cancer. Degrasyn, a small synthetic molecule, induces rapid degradation of c-Myc protein in MM-1 multiple myeloma and other tumor cell lines. Destruction of c-Myc by degrasyn requires the presence of a region of c-Myc between amino acid residues 316 and 378 that has not previously been associated with c-Myc stability. Degrasyn-induced degradation of c-Myc depends on proteasomes but is independent of the degron regions previously shown to be important for ubiquitin-mediated targeting and proteasomal destruction of the protein. Degrasyn-dependent c-Myc proteolysis is not mediated by any previously identified c-Myc regulatory mechanism, does not require new protein synthesis, and does not depend on the nuclear localization of c-Myc. Degrasyn reduced c-Myc levels in A375 melanoma cells and in A375 tumors in nude mice, and this activity correlated with tumor growth inhibition. Together, these results suggest that degrasyn reduces the stability of c-Myc in vitro and in vivo through a unique signaling process that uses c-Myc domains not previously associated with c-Myc regulation. [Cancer Res 2007;67(8):3912–8]