Modulation of basal cell fate during productive and transforming HPV-16 infection is mediated by progressive E6-driven depletion of Notch

The Journal of Pathology
Christian KranjecJohn Doorbar

Abstract

In stratified epithelia such as the epidermis, homeostasis is maintained by the proliferation of cells in the lower epithelial layers and the concomitant loss of differentiated cells from the epithelial surface. These differentiating keratinocytes progressively stratify and form a self-regenerating multi-layered barrier that protects the underlying dermis. In such tissue, the continual loss and replacement of differentiated cells also limits the accumulation of oncogenic mutations within the tissue. Inactivating mutations in key driver genes, such as TP53 and NOTCH1, reduce the proportion of differentiating cells allowing for the long-term persistence of expanding mutant clones in the tissue. Here we show that through the expression of E6, HPV-16 prevents the early fate commitment of human keratinocytes towards differentiation and confers a strong growth advantage to human keratinocytes. When E6 is expressed either alone or with E7, it promotes keratinocyte proliferation at high cell densities, through the combined inactivation of p53 and Notch1. In organotypic raft culture, the activity of E6 is restricted to the basal layer of the epithelium and is enhanced during the progression from productive to abortive or transforming HP...Continue Reading

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Citations

Mar 1, 2018·Journal of Dental Research·T Fukusumi, J A Califano
Apr 18, 2020·Cytopathology : Official Journal of the British Society for Clinical Cytology·Aslam ShirazJohn Doorbar
Apr 11, 2018·Frontiers in Microbiology·Carlotta OliveroGirish K Patel
Mar 24, 2018·Frontiers in Microbiology·Jordan M MeyersKarl Munger
Nov 10, 2020·Epigenetics : Official Journal of the DNA Methylation Society·Maria Rosa BuenahoraSandra J Perdomo
Nov 25, 2020·Current Protocols in Microbiology·Robert JacksonKoenraad Van Doorslaer
Mar 16, 2021·Tumour Virus Research·Arushi VatsLawrence Banks
Oct 22, 2019·Experimental Cell Research·Calvin RodriguesSudhir Krishna
Aug 19, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Rodrigo Pinheiro AraldiEdislane Barreiros de Souza

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Methods Mentioned

BETA
nuclear translocation
FACS
transfection
PCR

Software Mentioned

ImageJ

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