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Mutational analysis of the discs large tumour suppressor identifies domains responsible for human papillomavirus type 18 E6-mediated degradation

Instituto de Biologia Molecular y Celular de Rosario (IBR-CONICET), Departamento de Microbiologia, Facultad de Ciencias Bioquimicas, Suipacha 531, 2000 Rosario, Argentina¹
International Centre for Genetic Engineering and Biotechnology, Padriciano 99, I-34012 Trieste, Italy²

Author for correspondence: Daniela Gardiol. Fax +54 341 4804598. e-mail dgardiol{at}fbioyf.unr.edu.ar

The discs large (Dlg) tumour suppressor protein is targeted for ubiquitin-mediated degradation by the high-risk human papillomavirus E6 proteins. To understand further the mechanisms behind this, a mutational analysis of Dlg was undertaken. This study demonstrates that an intact PDZ domain 2 (PDZ2) on Dlg is necessary for the ability of E6 to bind and degrade Dlg. However, additional residues within the amino-terminal portion of Dlg are also required for optimal E6 activity. Stable cell lines expressing different Dlg mutants were also established and these confirm that Dlg is regulated intrinsically by the proteasome in the absence of E6; however, in this case, the sequences responsible for regulating Dlg stability lie predominantly within PDZ2. These results suggest that there are at least two mechanisms for regulating Dlg protein stability and that the pathways used by E6 are not necessarily the same as those used in the cell in its absence.

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