Abstract
Papillomavirus E6 oncoproteins associate with LXXLL motifs on target cellular proteins to alter their function. Using a proteomic approach, we found the E6 oncoproteins of cutaneous papillomaviruses Bovine Papillomavirus Type 1 (BPV-1) E6 and human papillomavirus (HPV) types 1 and 8 (1E6 and 8E6) associated with the MAML1 transcriptional co-activator. All three E6 proteins bind to an acidic LXXLL motif at the carboxy-terminus of MAML1 and repress transactivation by MAML1. MAML1 is best known as the co-activator and effector of NOTCH-induced transcription, and BPV-1 E6 represses synthetic NOTCH-responsive promoters, endogenous NOTCH-responsive promoters, and is found in a complex with MAML1 in stably transformed cells. BPV-1-induced papillomas show characteristics of repressed NOTCH signal transduction, including suprabasal expression of integrins, talin and basal type keratins, and delayed expression of the NOTCH-dependent HES1 transcription factor. These observations give rise to a model whereby papillomavirus oncoproteins, including BPV-1 E6, and the cancer-associated HPV-8 E6 repress NOTCH-induced transcription, thereby delaying keratinocyte differentiation.
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Acknowledgements
SVP, NB and CL were supported by NIH grants (CA120352 and CA08093) to SVP, and institutional support from the University of Virginia and the Department of Pathology Mass Spectrometry Facility. AEW is supported by the Swedish Research Council. We would like to thank Janet Cross and Benjamin Purow at UVA for helpful discussions and critical reading of the manuscript.
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Dr Vande Pol's work has been funded by the NIH. The authors declare no conflict of interest.
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Brimer, N., Lyons, C., Wallberg, A. et al. Cutaneous papillomavirus E6 oncoproteins associate with MAML1 to repress transactivation and NOTCH signaling. Oncogene 31, 4639–4646 (2012). https://doi.org/10.1038/onc.2011.589
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DOI: https://doi.org/10.1038/onc.2011.589
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