The role of viruses in cell transformation and oncogenesis

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Abstract

The data of modern scientific literature characterizing individual mechanisms of transformation of normal cells and various stages of oncogenesis associated with viruses were analyzed. The data of sequencing of tumor genomes and amino acid sequences indicate that most tumors are a consequence of the accumulation of sequential mutations, a significant contribution to the formation of which was made by oncogenic viruses. Processes that alter or impair the functioning of signaling pathways can contribute to transformation and oncogenesis. The phosphorylation of the ribosomal protein S6 by protein kinase B, which increases the speed, and prolongs the translation time, is critical in oncogenesis. Protein kinase B inhibits the processes of apoptosis, participates in the regulation of the cell cycle, and regulates tissue growth; an increased level of this protein is found in various tumors. Transformation and tumor-associated processes are the result of a combination of dominant mutations with increased function of proto-oncogenes and recessive mutations with a loss of function of tumor suppressor genes encoding proteins that block cell cycle progression. The function of any gene product can be altered by oncogenic viruses. Transforming proteins alter cell proliferation with a limited set of molecular mechanisms. The integration of proviral deoxyribonucleic acid in a specific region of the cellular genome contributes to the induction of tumor-associated processes by non-transductive viruses. Cellular oncogenes induce signaling at various stages of the cell cycle, which ultimately leads to its dysregulation and progression. In cell transformation, the interaction of E1A viral proteins with tumor suppressors RB, histone acetyltransferase p300/CVR, and inhibitors of cyclin-dependent kinases p27 and p21 is crucial. Virus-transforming proteins have various properties, from changing the sequences of primary amino acids to inducing various variants of biochemical activity. Most tumors induced by non-transductive retroviruses result from increased transcription of cellular genes (myc) located in close proximity to integrated proviruses. Latent membrane protein 1 is an integral protein of the plasma membrane and functions as a constitutively active receptor and facilitates the transition from a latent course of infection to a lytic one. In the absence of a ligand, this protein oligomerizes, and activates proteins that control cell proliferation and survival.

About the authors

Alexander V. Moskalev

Kirov Military Medical Academy

Author for correspondence.
Email: alexmav195223@yandex.ru
ORCID iD: 0000-0002-3403-3850
SPIN-code: 8227-2647

MD, Dr. Sci. (Med.), professor

Russian Federation, Saint Petersburg

Boris Yu. Gumilevsky

Kirov Military Medical Academy

Email: alexmav195223@yandex.ru
SPIN-code: 3428-7704
Scopus Author ID: 6602391269
ResearcherId: J-1841-2017

MD, Dr. Sci. (Med.), professor

Russian Federation, Saint Petersburg

Vasiliy Ya. Apchel

Kirov Military Medical Academy; Herzen State Pedagogical University of Russia

Email: alexmav195223@yandex.ru
ORCID iD: 0000-0001-7658-4856
SPIN-code: 4978-0785
Scopus Author ID: 6507529350
ResearcherId: Е-8190-2019

MD, Dr. Sci. (Med.), professor

Russian Federation, Saint Petersburg; Saint Petersburg

Vasiliy N. Tsygan

Kirov Military Medical Academy

Email: alexmav195223@yandex.ru
ORCID iD: 0000-0003-1199-0911
SPIN-code: 7215-6206

MD, Dr. Sci. (Med.), professor

Russian Federation, Saint Petersburg

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Supplementary files

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2. Fig. 1. Signaling pathways contributing to an increase in cell size and mass (according to J. Flint, Vincent R. Racaniello, G. Rall, Th. Hatzoocannon, 2020)

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3. Fig. 2. The mammalian cyclin-CDK cell cycle engine: а — phases of the cell cycle are indicated on a circle. The progressive accumulation of specific cyclins and cyclin-dependent kinases (CDKs) is represented by expanding arrows that mark the time of abrupt disappearance; b — secretion, accumulation, and biological effects of both cyclins and CDKs are regulated by numerous mechanisms. Green arrows and red bars indicate activating and inhibitory effects, interactions, or post-translational modifications (according to J. Flint, Vincent R. Racaniello, G. Rall, Th. Hatzoocannon, 2020)

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4. Fig. 3. A model of paracrine oncogenesis caused by products of type 8 HCV gene (according to J. Flint, Vincent R. Racaniello, G. Rall, Th. Hatzoocannon, 2020)

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5. Fig. 4. Constitutive activation of the cell membrane by Epstein–Barr virus protein 1: а — Summary of transcriptional and other regulators that are stimulated or repressed by signaling from LMP-1; b — LMP-1, which possesses six membrane-spanning segments but no large extracellular domain, oligomerizes in the absence of ligand, a property represented by the LMP-1 dimer depicted. When localized to the plasma membrane, the C-terminal segment of LMP-1 to which cellular proteins bind is sufficient for both activation of cellular transcriptional regulators and immortalization of B cells. The long cytoplasmic C-terminal domain of the viral protein contains three segments implicated in the activation of signaling, designated C-terminal activation regions (CTARs) 1 and 2, and the intervening proline-rich repeats. As shown, multiple members of the tumor necrosis factor receptor-associated protein family (TRAFs) bind to CTAR-1, leading to activation of the protein kinase NIK (NF-KB-inducing kinase) and IkK (Ik-kinase), and ultimately of NF-kB. The CTAR-2 domain of LMP-1 further induced activation of NF-kB via association with TRADD and TRAF-6. Moreover, it is responsible for the activation of AP-1 via the JUN N-terminal kinase pathway. Additionally, the TRAF-binding domain of CTAR-1 induces the activation of the MAP kinase cascade, whereas the proline-rich repeat region is crucial for the activation of JAK3 and STATs. These responses to LMP-1 are required for the transformation of rat fibroblasts. (according to J. Flint, Vincent R. Racaniello, G. Rall, Th. Hatzoocannon, 2020)

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Copyright (c) 2023 Moskalev A.V., Gumilevsky B.Y., Apchel V.Y., Tsygan V.N.

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

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