Human papillomavirus 16E6 and NFX1-123 potentiate Notch signaling and differentiation without activating cellular arrest.
High-risk human papillomavirus (HR HPV) oncoproteins bind host cell proteins to dysregulate and uncouple apoptosis, senescence, differentiation, and growth. These pathways are important for both the viral life cycle and cancer development. HR HPV16 E6 (16E6) interacts with the cellular protein NFX1-123, and they collaboratively increase the growth and differentiation master regulator, Notch1. In 16E6 expressing keratinocytes (16E6 HFKs), the Notch canonical pathway genes Hes1 and Hes5 were increased with overexpression of NFX1-123, and their expression was directly linked to the activation or blockade of the Notch1 receptor. Keratinocyte differentiation genes Keratin 1 and Keratin 10 were also increased, but in contrast their upregulation was only indirectly associated with Notch1 receptor stimulation and was fully unlinked to growth arrest, increased p21(Waf1/CIP1), or decreased proliferative factor Ki67. This leads to a model of 16E6, NFX1-123, and Notch1 differently regulating canonical and differentiation pathways and entirely uncoupling cellular arrest from increased differentiation.
Center for Global Infectious Disease Research, Seattle Children׳s Research Institute, 1900 Ninth Ave., Seattle, WA 98101, USA.
Portia A
PA
Vliet-Gregg
Center for Global Infectious Disease Research, Seattle Children׳s Research Institute, 1900 Ninth Ave., Seattle, WA 98101, USA.
Jennifer R
JR
Hamilton
Center for Global Infectious Disease Research, Seattle Children׳s Research Institute, 1900 Ninth Ave., Seattle, WA 98101, USA; Department of Pediatrics, Division of Adolescent Medicine, University of Washington, Seattle WA, USA. Electronic address: rkatzen@uw.edu.
Rachel A
RA
Katzenellenbogen
D002454:Cell Differentiation; D002478:Cells, Cultured; D054884:Host-Pathogen Interactions; D052162:Human papillomavirus 16 / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000821:virology; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction
C068651:E6 protein, Human papillomavirus type 16; C492666:NFX1 protein, human; C497761:NOTCH1 protein, human; D009856:Oncogene Proteins, Viral; D051881:Receptor, Notch1; D012097:Repressor Proteins
Cell cycle; Differentiation; HPV E6; Keratinocytes; NFX1-123; Notch