engleski

PDZ-domain Containing Protein NHERF-2 is a Novel Target of Human Papillomavirus type 16 (HPV-16) and HPV- 18

Cancer causing HPV E6 oncoproteins have a Class I PDZ- binding motif (PBM) on their C-termini, which play critical roles that are related to HPV life cycle and HPV-induced malignancies. E6 oncoproteins use these PBMs to interact and target for a proteasome mediated degradation a plethora of cellular substrates that contain PDZ domains and are involved in the regulation of various cellular pathways. In this study, we show that both HPV-16 and HPV-18 E6 can interact with Na+/H+ exchange regulatory factor 2 (NHERF-2), a PDZ domain containing protein, which among other cellular functions also behaves as a tumor suppressor that regulates endothelial proliferation. The interaction between the E6 oncoproteins and NHERF-2 is PBM dependent and this consequently results in a proteasome-mediated degradation of NHERF-2. We further confirmed this effect in cells derived from HPV-16 and HPV- 18 positive cervical tumors, where we show that NHERF-2 protein turnover is increased in the presence of E6. Finally, our data indicate that E6-mediated NHERF-2 degradation results in p27 downregulation and cyclin D1 upregulation, which leads to an accelerated cellular proliferation. To our knowledge, this is the first report which demonstrates that E6 oncoproteins can stimulate cell proliferation by indirectly regulating p27 via targeting a PDZ-domain containing protein.

HPV ; E6 oncoprotein ; cervical cancer ; NHERF-2 ; p27 ; cyclin D1 ; cell proliferation

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