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Molecular and Cellular Biology, June 2009, p. 3424-3434, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.01535-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Identification of Domains Responsible for Ubiquitin-Dependent Degradation of dMyc by Glycogen Synthase Kinase 3β and Casein Kinase 1 Kinases ^,

Margherita Galletti,^2, Sara Riccardo,^1, Federica Parisi,^1,5 Carlina Lora,¹ Mahesh Kumar Saqcena,³ Leinny Rivas,¹ Bonnie Wong,¹ Alexis Serra,¹ Florenci Serras,⁴ Daniela Grifoni,⁵ PierGiuseppe Pelicci,⁶ Jin Jiang,⁷ and Paola Bellosta^1*

Department of Biology, City College of the City University of New York, New York, New York,¹ Department of Medical Science, University of Modena, Modena, Italy,² Department of Chemistry and Biochemistry, Queens College of the City University of New York, New York, New York,³ Department of Genetics, University of Barcelona, Barcelona, Spain,⁴ Alma Mater Studiorum, Department of Experimental Pathology, Bologna, Italy,⁵ European Institute of Oncology, Milan, Italy,⁶ Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas⁷

Received 2 October 2008/ Returned for modification 3 November 2008/ Accepted 27 March 2009

In the present study, we report that ubiquitin-mediated degradation of dMyc, the Drosophila homologue of the human c-myc proto-oncogene, is regulated in vitro and in vivo by members of the casein kinase 1 (CK1) family and by glycogen synthase kinase 3β (GSK3β). Using Drosophila S2 cells, we demonstrate that CK1 promotes dMyc ubiquitination and degradation with a mechanism similar to the one mediated by GSK3β in vertebrates. Mutation of ck1 or - or sgg/gsk3β in Drosophila wing imaginal discs results in the accumulation of dMyc protein, suggesting a physiological role for these kinases in vivo. Analysis of the dMyc amino acid sequence reveals the presence of conserved domains containing potential phosphorylation sites for mitogen kinases, GSK3β, and members of the CK1 family. We demonstrate that mutations of specific residues within these phosphorylation domains regulate dMyc protein stability and confer resistance to degradation by CK1 and GSK3β kinases. Expression of the dMyc mutants in the compound eye of the adult fly results in a visible defect that is attributed to the effect of dMyc on growth, cell death, and inhibition of ommatidial differentiation.

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* Corresponding author. Mailing address: Department of Biology, City College of the City University of New York, 138th at Convent Ave., New York, NY 10031. Phone: (212) 650-8479. Fax: (212) 650-8585. E-mail: pbellost{at}sci.ccny.cuny.edu

Published ahead of print on 13 April 2009.

Supplemental material for this article may be found at http://mcb.asm.org/.

M.G. and S.R. contributed equally to this study.

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Molecular and Cellular Biology, June 2009, p. 3424-3434, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.01535-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.