Academic Journal
The effect of phosphorylation efficiency on the oncogenic properties of the protein E7 from high-risk HPV
| العنوان: | The effect of phosphorylation efficiency on the oncogenic properties of the protein E7 from high-risk HPV |
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| المؤلفون: | Madison Malone, Ava Maeyama, Naomi Ogden, Kayla N. Perry, Andrew Kramer, Caleb Bates, Camryn Marble, Ryan Orlando, Amy Rausch, Caleb Smeraldi, Connor Lowey, Bronson Fees, H. Jane Dyson, Michael Dorrell, Heidi Kast-Woelbern, Ariane L. Jansma |
| المصدر: | Virus Research, Vol 348, Iss , Pp 199446- (2024) |
| بيانات النشر: | Elsevier, 2024. |
| سنة النشر: | 2024 |
| المجموعة: | LCC:Microbiology LCC:Infectious and parasitic diseases |
| مصطلحات موضوعية: | Post-translational modification, Oncogenic Virus, pRb degradation, NMR (Nuclear Magnetic Resonance), Intrinsically disordered protein, Microbiology, QR1-502, Infectious and parasitic diseases, RC109-216 |
| الوصف: | The Human papillomavirus (HPV) causes tumors in part by hijacking the host cell cycle and forcing uncontrolled cellular division. While there are >200 genotypes of HPV, 15 are classified as high-risk and have been shown to transform infected cells and contribute to tumor formation. The remaining low-risk genotypes are not considered oncogenic and result in benign skin lesions. In high-risk HPV, the oncoprotein E7 contributes to the dysregulation of cell cycle regulatory mechanisms. High-risk E7 is phosphorylated in cells at two conserved serine residues by Casein Kinase 2 (CK2) and this phosphorylation event increases binding affinity for cellular proteins such as the tumor suppressor retinoblastoma (pRb). While low-risk E7 possesses similar serine residues, it is phosphorylated to a lesser degree in cells and has decreased binding capabilities. When E7 binding affinity is decreased, it is less able to facilitate complex interactions between proteins and therefore has less capability to dysregulate the cell cycle. By comparing E7 protein sequences from both low- and high-risk HPV variants and using site-directed mutagenesis combined with NMR spectroscopy and cell-based assays, we demonstrate that the presence of two key nonpolar valine residues within the CK2 recognition sequence, present in low-risk E7, reduces serine phosphorylation efficiency relative to high-risk E7. This results in significant loss of the ability of E7 to degrade the retinoblastoma tumor suppressor protein, thus also reducing the ability of E7 to increase cellular proliferation and reduce senescence. This provides additional insight into the differential E7-mediated outcomes when cells are infected with high-risk verses low-risk HPV. Understanding these oncogenic differences may be important to developing targeted treatment options for HPV-induced cancers. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1872-7492 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S0168170224001394; https://doaj.org/toc/1872-7492 |
| DOI: | 10.1016/j.virusres.2024.199446 |
| URL الوصول: | https://doaj.org/article/02f1bcb4f5b44a5cbcbc25e96d5bae9a |
| رقم الانضمام: | edsdoj.02f1bcb4f5b44a5cbcbc25e96d5bae9a |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 18727492 |
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| DOI: | 10.1016/j.virusres.2024.199446 |