Abstract
Several experimental strategies in the treatment of cancer include drug alteration of cell cycle regulatory pathways as a useful strategy. Extra-ribosomal functions of human ribosomal protein L3 (uL3) may affect DNA repair, cell cycle arrest and apoptosis. In the present study, we demonstrated that uL3 is required for the activation of G1/S transition genes. Luciferase assays established that uL3 negatively regulates the activity of E2F1 promoter. Induced ribosome-free uL3 reduces Cyclin D1 mRNA and protein levels. Using protein/protein immunoprecipitation methods, we demonstrated that uL3 physically interacts with PARP-1 affecting E2F1 transcriptional activity. Our findings led to the identification of a new pathway mediated by uL3 involving E2F1 and Cyclin D1 in the regulation of cell cycle progression.
Highlights
The cell cycle is a regulatory process by which cells grow, replicate their DNA and divide
Cell cycle progression through G1 phase is an activity strictly controlled in cells, it can be separated in early-G1 trascriptional activation of early genes, mid-G1 activation of cyclin D/cdk4/6, and late-G1 activation of cyclin E/cdk[211]
To further characterize the effects of uL3 silencing, we investigated the effect of low levels of uL3 on cell proliferation, cell motility and epithelial–mesenchymal transition (EMT), a migratory cellular program associated with tumor development and metastasis
Summary
The cell cycle is a regulatory process by which cells grow, replicate their DNA and divide It is controlled by a complex series of multiple, different signaling pathways. Perturbations of rRNA synthesis and/or processing are closely related to cell cycle alteration and cancer progression[2]. Nucleolar stress has been demonstrated to activate p53-dependent and p53-independent stress response signaling pathways with consequent cell cycle arrest and/or apoptosis[5]. A group of ribosomal proteins (RP) affect cell cycle progression through the activation of different mechanisms. The phosphorylation of retinoblastoma protein (pRb) family mediated by cdk/ cyclin complexes is necessary for the transition from the G1 to the S phase of cell cycle. E2F1 function is subject to complex control mechanisms during cell cycle progression. The comprehension of the molecular mechanisms controlling G1/S transition is crucial to identify new strategies to maintain a correct regulation of cell cycle
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