HPV E6 specifically targets different cellular pools of its PDZ domain-containing tumour suppressor substrates for proteasome-mediated degradation.
The high-risk HPV E6 proteins have been shown to direct the degradation of a variety of cellular proteins that contain PDZ domains. Although some of these proteins are involved in regulating processes of cell growth and polarity in Drosophila, little is known about their function in higher eukaryotic epithelial cells. In HPV-containing cells derived from cervical tumours, we find that the patterns of expression of the E6 targets hDlg (discs large), hScrib (Scribble), and MUPP1 are consistent with their being substrates for E6-induced degradation. It is also clear that, in the case of hDlg, E6 is specifically targeting nuclear pools of the protein rather than membrane-bound forms. We have also analysed the activity of a subset of E6 target proteins in the suppression of oncogene-induced cell transformation. Interestingly, Dlg, MAGI-1 and MUPP1 efficiently suppressed cell transformation, while MAGI-2 and MAGI-3 were ineffective in this assay. These results suggest that in the context of HPV-induced transformation Dlg, MAGI-1 and MUPP1 can function as tumour suppressors.
Massimi
Paola
P
International Centre for Genetic Engineering and Biotechnology, Padriciano 99, Trieste I-34012, Italy.
Gammoh
Noor
N
Thomas
Miranda
M
Banks
Lawrence
L
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000502:physiology*; D003593:Cytoplasm / Q000378:metabolism; D000074288:Discs Large Homolog 1 Protein; D005260:Female; D051528:Guanylate Kinases; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009097:Multienzyme Complexes / Q000502:physiology*; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; C068651:E6 protein, Human papillomavirus type 16; C111442:MPDZ protein, human; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D009856:Oncogene Proteins, Viral; D011506:Proteins; D012097:Repressor Proteins; C480591:SCRIB protein, human; D025521:Tumor Suppressor Proteins; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex