title: Cutaneous papillomavirus E6 oncoproteins associate with MAML1 to repress transactivation and NOTCH signaling.
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.
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA 22908-0904, USA.
authors.forename: N
authors.initials: N
authors.lastname: Brimer
authors.forename: C
authors.initials: C
authors.lastname: Lyons
authors.forename: A E
authors.initials: AE
authors.lastname: Wallberg
authors.forename: S B
authors.initials: SB
authors.lastname: Vande Pol
mesh_terms: D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D027383:Papillomaviridae / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C430872:MAML1 protein, human; D051880:Receptors, Notch; D014157:Transcription Factors; D014764:Viral Proteins