Human papillomavirus type 16 E6 amino acid 83 variants enhance E6-mediated MAPK signaling and differentially regulate tumorigenesis by Notch signaling and oncogenic Ras

Oishee Chakrabarti, Karthikeyan Veeraraghavalu, Vinay Tergaonkar, Yun Liu, Elliot Androphy, Margaret A. Stanley, Sudhir Krishna

Research output: Contribution to journalArticle

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Abstract

Oncogenically high-risk human papillomaviruses (HPVs) are causally associated with the progression of major human neoplasia-like cancers of the cervix. Several studies have defined functions of the key E6 and E7 oncoproteins in epithelial cell immortalization. The roles of these oncogenes in the progression of immortalized epithelial cells to invasive tumors are still poorly understood. Here, we establish a novel link between the E6 oncoprotein and activation of mitogen-activated protein kinase (MAPK) signaling and show that this signaling involves Rap1. We find that activated MAPK signaling cooperates with deregulated Notch1 signaling to recreate features of HPV-driven invasive cervical carcinomas. We extend our analysis to evaluate an E6 (amino acid [aa] 83) variant that has been linked to invasive tumors. The variant enhances MAPK signaling and cooperative transformation with deregulated Notch1 signaling. Unlike E6, this variant surprisingly inhibits oncogenic Ras-mediated transformation. Our data reveal that the quantitative differences in activation of MAPK signaling by E6 and its variant correlate with differences in cooperative transformation with other signaling pathways, thus suggesting that thresholds of MAPK activation may define permissive conditions for other signaling pathways in tumorigenesis. Epidemiological studies have suggested the importance of E6 aa 83 variants in invasive carcinomas; our data support a key deterministic role for this variant in human cervical tumorigenesis. These observations, along with our recent data showing that deregulated Notch signaling activates phosphatidylinositol 3-kinase signaling, strengthen the possibility of the existence of Ras-independent mechanisms to recreate signaling through classical Ras effector pathways.

Original languageEnglish (US)
Pages (from-to)5934-5945
Number of pages12
JournalJournal of Virology
Volume78
Issue number11
DOIs
StatePublished - Jun 2004
Externally publishedYes

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Human papillomavirus 16
Papillomaviridae
Mitogen-Activated Protein Kinases
mitogen-activated protein kinase
carcinogenesis
Carcinogenesis
Amino Acids
amino acids
uterine cervical neoplasms
Oncogene Proteins
cooperatives
neoplasms
epithelial cells
Epithelial Cells
Phosphatidylinositol 3-Kinase
Carcinoma
Neoplasms
oncogenes
phosphatidylinositol 3-kinase
Oncogenes

ASJC Scopus subject areas

  • Immunology

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Human papillomavirus type 16 E6 amino acid 83 variants enhance E6-mediated MAPK signaling and differentially regulate tumorigenesis by Notch signaling and oncogenic Ras. / Chakrabarti, Oishee; Veeraraghavalu, Karthikeyan; Tergaonkar, Vinay; Liu, Yun; Androphy, Elliot; Stanley, Margaret A.; Krishna, Sudhir.

In: Journal of Virology, Vol. 78, No. 11, 06.2004, p. 5934-5945.

Research output: Contribution to journalArticle

Chakrabarti, Oishee ; Veeraraghavalu, Karthikeyan ; Tergaonkar, Vinay ; Liu, Yun ; Androphy, Elliot ; Stanley, Margaret A. ; Krishna, Sudhir. / Human papillomavirus type 16 E6 amino acid 83 variants enhance E6-mediated MAPK signaling and differentially regulate tumorigenesis by Notch signaling and oncogenic Ras. In: Journal of Virology. 2004 ; Vol. 78, No. 11. pp. 5934-5945.
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