Elena Kashuba Project
Molecular mechanisms of cell transformation
Role of EBNA-binding cellular proteins in EBV-induced cell transformation:
The discovery of molecular mechanisms of cell transformation is one of the most important and intricate questions of modern cell biology. We are using the Epstein-Barr virus (EBV)-induced B-cell immortalization as a model system. It is clear now that EBV exploits the normal signaling pathways of the B lymphocyte and the six growth transformation associated EBNAs promote cell proliferation and protect from apoptosis. Our project is aimed on elucidation of the role of cellular proteins that bind to EBNAs in cell transformation. Over the last few years, we have discovered 17 previously unknown interactions between three transforming proteins - EBNA-3, EBNA-5 and EBNA-6 and cellular proteins. Studying the influence of EBV on the RB – E2F1 pathway, we have found that EBNA-6 interacts with RB-associated protein, mitochondrial ribosomal protein MRPS18-2 (S18-2), leading to the liberation of E2F1. This stimulates the entry of the cell into the S-phase.
Role of interplay between MRPS18-2 and RB proteins in development of child tumors and in control on cell stemness and differentiation:
S18 family of mitochondrial ribosomal proteins (MRPS18, S18) consists of three members, S18-1 to -3. Earlier, we found that overexpression of S18-2 protein resulted in immortalization and eventual transformation of primary rat fibroblasts.
We found that the S18-2 is mutated at a higher rate in human cancers, compared with S18-1 and -3 proteins. Moreover, the evolutionarily conserved residue, Gly132 of S18-2, shows genetic polymorphism in colon adenocarcinomas, that was confirmed by direct DNA sequencing.
Recently, we have shown that the level of S18-2 protein increased in endometrial cancer compared with the normal endometrium and hyperplasia. Importantly, high expression of free E2F1 correlates well with high S18-2 expression. The endometrial cancer cell line HEC-1-A, which overexpresses S18-2 constitutively, showed an increased proliferation capacity in vitro and in vivo (in SCID mice). Moreover, pan-keratin, beta-catenin and E-cadherin signals are diminished in these cells, compared to the parental HEC-1-A line, in contrast to vimentin signal that is increased. This may be associated with epithelial-mesenchymal cell transition.
We are currently investigating the role of S18-2 protein in cell immortalization and embryogenesis
The European meeting on epstein barr virus and associated malignances took place in June 2015
Elena Kashuba Publications
Do MRPS18-2 and RB proteins cooperate to control cell stemness and differentiation, preventing cancer development?
Exp. Oncol. 2017 Mar;39(1):12-16
S18 family of mitochondrial ribosomal proteins: evolutionary history and Gly132 polymorphism in colon carcinoma.
Oncotarget 2016 Aug;7(34):55649-55662
Role of the RB-Interacting Proteins in Stem Cell Biology.
Adv. Cancer Res. 2016 ;131():133-57
Mitochondrial ribosomal protein S18-2 is highly expressed in endometrial cancers along with free E2F1.
Oncotarget 2016 Apr;7(16):22150-8
DNA Tumor Viruses and Cell Metabolism.
Oxid Med Cell Longev 2016 ;2016():6468342
Different Mechanisms of Regulation of the Warburg Effect in Lymphoblastoid and Burkitt Lymphoma Cells.
PLoS ONE 2015 ;10(8):e0136142
Mitochondrial ribosomal protein S18-2 evokes chromosomal instability and transforms primary rat skin fibroblasts.
Oncotarget 2015 Aug;6(25):21016-28
Stem cell gene expression in MRPS18-2-immortalized rat embryonic fibroblasts.
Cell Death Dis 2012 Jan;3():e357
Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes.
Cell. Mol. Life Sci. 2010 Dec;67(24):4249-56
Epstein-Barr virus-encoded EBNA-5 forms trimolecular protein complexes with MDM2 and p53 and inhibits the transactivating function of p53.
Int. J. Cancer 2011 Feb;128(4):817-25
Euroethics--a database network on biomedical ethics.
Health Info Libr J 2006 Sep;23(3):169-78
Interaction of Epstein-Barr virus (EBV) with human B-lymphocytes.
Biochem. Biophys. Res. Commun. 2010 May;396(1):67-73
Full Publication List
Project Group Members
Photo Archive of Group Members