Abstract
We have shown earlier that overexpression of the human mitochondrial ribosomal protein MRPS18-2 (S18-2) led to immortalization of primary rat embryonic fibroblasts. The derived cells expressed the embryonic stem cell markers, and cellular pathways that control cell proliferation, oxidative phosphorylation, cellular respiration, and other redox reactions were activated in the immortalized cells.Here we report that, upon overexpression of S18-2 protein, primary rat skin fibroblasts underwent cell transformation. Cells passed more than 300 population doublings, and two out of three tested clones gave rise to tumors in experimental animals. Transformed cells showed anchorage-independent growth and loss of contact inhibition; they expressed epithelial markers, such as E-cadherin and β-catenin. Transformed cells showed increased telomerase activity, disturbance of the cell cycle, and chromosomal instability. Taken together, our data suggest that S18-2 is a newly identified oncoprotein that may be involved in cancerogenesis.
Highlights
Understanding the molecular mechanisms underlying cell transformation is one of the most important and intricate challenges of modern cancer biology
We have reported earlier that the mitochondrial ribosomal protein MRPS18-2 (S18-2, NP_054765) binds to RB [6] and prevents the formation of the E2F1– RB complex that leads to elevated levels of free E2F1 www.impactjournals.com/oncotarget protein in the nucleus and the subsequent promotion of S phase entry [7]
Primary rat embryonic fibroblasts (REFs) turned into stem-like cells upon S18-2 overexpression. To determine whether this effect is common in other cells, 2–5×105 primary rat skin fibroblasts (RSFs) were grown in a 7.5-cm-diameter petri dish and transfected with a plasmid encoding the GFP-fused S18-2
Summary
Understanding the molecular mechanisms underlying cell transformation is one of the most important and intricate challenges of modern cancer biology. The infected cells could not produce new viral particles but became transformed and lost normal control of cell growth (discussed in [2]) In this model, a few characteristics distinguished transformed cells from primary adherent cells: the cells changed morphologically, became immortal, lost contact inhibition, and acquired the ability for anchorage-independent growth. A few characteristics distinguished transformed cells from primary adherent cells: the cells changed morphologically, became immortal, lost contact inhibition, and acquired the ability for anchorage-independent growth All of these features were easy to monitor because the cells overcame the Hayflick limit of division (see [3]), formed foci in the culture and in soft agar, and gave rise to tumors in animals
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