Human papillomavirus type 8 oncoproteins E6 and E7 cooperate in downregulation of the cellular checkpoint kinase-1
| Autor: | Baki Akgül, Matthias Kirschberg, Martin Hufbauer, Alan Storey |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Cancer Research
DNA damage Autophagy Bafilomycin Cell cycle Biology Cell biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Oncology Downregulation and upregulation chemistry 030220 oncology & carcinogenesis Gene expression CHEK1 biological phenomena cell phenomena and immunity Psychological repression |
| Zdroj: | International Journal of Cancer. 145:797-806 |
| ISSN: | 0020-7136 |
| Popis: | Human papillomavirus 8 (HPV8) is associated with the development of squamous cell carcinoma (SCC) of the skin. HPV-infected keratinocytes are able to override normal checkpoint control mechanisms and sustain cell cycle activity, allowing for synthesis of cellular proteins necessary for viral genome amplification. To study how HPV8 may disrupt cell cycle control, we analyzed the impact of HPV8 early gene expression on one of the key regulators of cell cycle and DNA damage response, checkpoint kinase-1 (CHK1). We found that expression of E1, E1E4, E2, E6 or E7 individually did not affect CHK1; however, keratinocytes expressing the complete early genome region (CER) of HPV8 showed a profound loss of CHK1 protein levels, that proved to be mediated by E6E7 co-expression. Neither CHK1 promoter regulation nor the ubiquitin-proteasome pathway are involved in HPV8-mediated CHK1 repression. However, CHK1 protein repression in organotypic skin cultures was paralleled by downregulation of the autophagy marker LC3B. Treatment of HPV8-CER expressing cells with the autophagy inhibitor Bafilomycin A1 rescued CHK1 expression and led to LC3B accumulation. Taken together, our data implicate that CHK1 autophagic degradation is enhanced by HPV8, which may contribute to the oncogenic potential of the virus. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text