The high‐risk HPV E6 proteins modify the activity of the eIF4E protein via the MEK/ERK and AKT/PKB pathways
| Autor: | Marcela Lizano, Vicente Morales-García, Eduardo Martínez-Abundis, Adriana Contreras-Paredes, Fernanda Hernandez-Landero, Erick Natividad De la Cruz-Hernández, Nancy Patricia Gómez-Crisóstomo |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway E6 oncoprotein General Biochemistry Genetics and Molecular Biology Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Cyclin D1 Protein biosynthesis Humans human papillomavirus Post-transcriptional regulation Protein kinase B Cells Cultured Research Articles PI3K/AKT/mTOR pathway Mitogen-Activated Protein Kinase Kinases post‐transcriptional regulation Chemistry EIF4E virus diseases Oncogene Proteins Viral Cell biology DNA-Binding Proteins Repressor Proteins Eukaryotic Initiation Factor-4E 030104 developmental biology eIF4E 030220 oncology & carcinogenesis Phosphorylation Female Proto-Oncogene Proteins c-akt Research Article |
| Zdroj: | FEBS Open Bio |
| ISSN: | 2211-5463 |
| Popis: | In this study, we show that high‐risk E6 oncogenes (HPV16, HPV‐18, and HPV52) regulate eIF4E activity through downstream targets of PI3K/AKT/mTORC1 and MEK/ERK pathways, increasing translation of cellular proteins regulated by CAP‐dependent mechanisms (CCND1 and ODC1). The pharmacological inhibition of eIF4E phosphorylation by Ribavirin highlights the utility of this approach for the treatment of cervical cancer. Previous studies have proposed that the human papillomavirus (HPV) E6 oncoproteins modify the transcriptional activity of eIF4E through mechanisms dependent on p53 degradation. However, the effect of these oncoproteins on pathways regulating the activity of the eIF4E protein remains poorly understood. Hence, we investigated the mechanisms whereby E6 proteins regulate the activity of the eIF4E protein and its effect on target genes. Overexpression of E6 constructs (HPV‐6, HPV‐16, HPV‐18, and HPV52) showed that E6 oncoproteins increased phosphorylation of the eIF4E protein (Serine‐209). This result was mainly mediated by phosphorylation of the 4EBP1 protein via the PI3K/AKT pathway. Additionally, the pharmacological inhibition of eIF4E phosphorylation in cervical cancer cell lines substantially reduced the protein levels of CCND1 and ODC1, indicating that E6 of the high‐risk genotypes may modify protein synthesis of the eIF4E target genes by increasing the activity of the AKT and ERK pathways. |
| Databáze: | OpenAIRE |
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