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Báo cáo khoa học: Differential effects of Mxi1-SRa and Mxi1-SRb in Myc antagonism

Mxi1 belongs to the Myc-Max-Mad transcription factor network. Two Mxi1 protein isoforms, Mxi1-SRaand Mxi1-SRb, have been described as sharing many biological properties. Here, we assign differential functions to these isoforms with respect to two distinct levels of Myc antagonism. | ỊFEBS Journal Differential effects of Mxi1-SRa and Mxi1-SRb in Myc antagonism Claire Dugast-Darzacq1 2 Thierry Grange2 and Nicole B. Schreiber-Agus1 1 Department of Molecular Genetics Albert Einstein College of Medicine Bronx NY USA 2 Institut Jacques Monod CNRS-Universites de Paris France Keywords GAPDH isoforms Mxi1 Myc REF assay Correspondence C. Dugast-Darzacq Institut Jacques Monod CNRS-Universites de PARIS 6 et 7 75251 Paris Cedex 05 France Fax 33 1 4427 5716 Tel 33 1 4427 5707 E-mail darzacq@ijm.jussieu.fr Received 14 March 2007 revised 12 July 2007 accepted 16 July 2007 doi 10.1111 j.1742-4658.2007.05992.x Mxil belongs to the Myc-Max-Mad transcription factor network. Two Mxil protein isoforms Mxi1-SRa and Mxi1-SRb have been described as sharing many biological properties. Here we assign differential functions to these isoforms with respect to two distinct levels of Myc antagonism. Unlike Mxi1-SRb Mxi1-SRa is not a potent suppressor of the cellular transformation activity of Myc. Furthermore although Mxi1-SRb exhibits a repressive effect on the MYC promoter in transient expression assays Mxi1-SRa activates this promoter. A specific domain of Mxi1-SRa contributes to these differences. Moreover glyceraldehyde-3-phosphate dehydrogenase interacts with Mxi1-SRa and enhances its ability to activate the Myc promoter. Our findings suggest that Mxi1 gains functional complexity by encoding isoforms with shared and distinct activities. Members of the Myc oncoprotein family function as transcription factors that control various aspects of cellular behavior including cell growth proliferation differentiation apoptosis genomic stability and tumorigenesis 1-4 . Deregulation of Myc contributes to the pathogenesis of a large proportion of human cancers 5 6 . This deregulation has been shown to occur at multiple levels including those that affect myc gene expression Myc protein stability and Myc biological activity. Normal regulation of Myc activity occurs by mechanisms that