Russo Giulia

Biography

-1986 Degree in Biological Sciences -1987 Enrollment to the profession of biologist -1987-1990 Student of the School of Specialization in General Pathology at the Faculty of Medicine of the University of Naples "Federico II -1990 Specialist Diploma in General Pathology discussing an experimental thesis titled: The vaccine virus as expression vector for recombinant human proteins.

Research Interest

a) Mechanisms for regulating cell growth in response to events that induce nucleolar stress The rpL3 protein belongs to a group of ribosomal proteins that do not only participate in the biosynthesis process of ribosomes but has a number of extra-ribosomal activity important in regulating different cellular processes. rpL3 acts as a crucial regulator of cell cycle, apoptosis and DNA repair by modulating the expression of p21 and CBS, key enzyme in H2S production. rpL3 also plays a critical role in cell response to ribosomal stress induced by drugs such as 5-fluorouracil, oxaliplatin and actinomycin D. In fact, in the cell lines of colon and lung cancer that do not express p53, the efficacy of the treatment pharmacological depends on the status of rpL3; in the absence of rpL3 these drugs are ineffective. It has been shown that a marked reduction in rpL3 expression levels is associated with an increase in PgP (P-glycoprotein 1) membrane pump levels. The ectopic expression of rpL3 reverses the chemo-resistant phenotype making cells sensitive to chemotherapy treatment. In particular, it has been observed that reuptake of rpL3 is associated with regulation of levels of reactive oxygen species (ROS), glutathione (GSH), cysteine ​​and glutamate content. At a molecular level, rpL3 has been shown to regulate the transcription of genes involved in response to oxidative stress. Specifically, rpL3 is capable of adjusting xCT and GST-a1 levels in response to 5-FU treatment. In resistant Calu-6 cells, an increase in mRNA levels for xCT and GST-a1 is observed, in contrast, the ectopic expression of rpL3 is associated with a decrease in the levels of these two proteins. This activity is independent of Nrf2, known transcriptional regulator of these genes. The collection of data allows to propose a model according to which chemoresistance is associated with a reduced expression of rpL3 and an increase in the activity of the genes involved in oxidative stress response. In particular, the reduction of intracellular levels of rpL3 transcriptional repressor is associated with an increase in expression of xCT and GST-a1 antioxidant genes. In addition, the negative regulation of rpL3 expression is associated with a hyper-expression of the PgP membrane pump involved in chemotherapy outflow chemotherapy. known transcriptional regulator of these genes. The collection of data allows to propose a model according to which chemoresistance is associated with a reduced expression of rpL3 and an increase in the activity of the genes involved in oxidative stress response. In particular, the reduction of intracellular levels of rpL3 transcriptional repressor is associated with an increase in expression of xCT and GST-a1 antioxidant genes. In addition, the negative regulation of rpL3 expression is associated with a hyper-expression of the PgP membrane pump involved in chemotherapy outflow chemotherapy. known transcriptional regulator of these genes. The collection of data allows to propose a model according to which chemoresistance is associated with a reduced expression of rpL3 and an increase in the activity of the genes involved in oxidative stress response. In particular, the reduction of intracellular levels of rpL3 transcriptional repressor is associated with an increase in expression of xCT and GST-a1 antioxidant genes. In addition, the negative regulation of rpL3 expression is associated with a hyper-expression of the PgP membrane pump involved in chemotherapy outflow chemotherapy. The collection of data allows to propose a model according to which chemoresistance is associated with a reduced expression of rpL3 and an increase in the activity of the genes involved in oxidative stress response. In particular, the reduction of intracellular levels of rpL3 transcriptional repressor is associated with an increase in expression of xCT and GST-a1 antioxidant genes. In addition, the negative regulation of rpL3 expression is associated with a hyper-expression of the PgP membrane pump involved in chemotherapy outflow chemotherapy. The collection of data allows to propose a model according to which chemoresistance is associated with a reduced expression of rpL3 and an increase in the activity of the genes involved in oxidative stress response. In particular, the reduction of intracellular levels of rpL3 transcriptional repressor is associated with an increase in expression of xCT and GST-a1 antioxidant genes. In addition, the negative regulation of rpL3 expression is associated with a hyper-expression of the PgP membrane pump involved in chemotherapy outflow chemotherapy. b ) NMD (nonsense-mediated mRNA decay): a new post-transcriptional mechanism for genes for ribosomal proteinsThe expression of genetic information is mediated by RNA molecules, whose accurate biogenesis is largely responsible for the accuracy of gene products. Eukaryotes have developed evolutionary mechanisms to produce quality control of mRNA products that trigger at various levels of post-transcriptional and translational processes, and ultimately determine the amount and quality of the protein produced. "Nonsense-mediated mRNA decay" (NMD) indicates a rapid and selective degradation of mRNAs containing a premature stop codon (PTC) resulting from a DNA mutation or a post-transcriptional maturation incomplete. However, recent data suggest that NMD can represent a more general and efficient post-transcriptional gene regulation mechanism, realized through the control of the embryos of mRNA isoforms produced for alternative splicing. The aim of this research project was to study the importance of this process in regulating the expression of genes for ribosomal proteins in mammals. To this end, the expression profile of some human ribosomal genes in cells where the NMD pathway was pharmacologically blocked was analyzed. An experimental system has been developed that has enabled in vivo to inactivate NMD by means of the Calu-6 cell line (human lung adenocarcinoma) with specific drugs: cycloheximide, protein synthesis inhibitor, and wortmannina , an inhibitor of the PIK-kinase activity of the hSMG-1 protein involved in the NMD process. With this approach, alternate mRNAs of rpL3 and rpL12 genes were found and identified by Northern blotting and RT-PCR experiments. It has been shown that such isoforms are natural targets of NMD; in fact, they contain PTCs resulting from an alternative splicing event that causes incomplete removal of an intron. The bioinformatic analysis showed that the alternative splicing described for rpL3 and rpL12 human genes is stored between mammals (mouse, bovine). In addition, we investigated the role of r-proteins in the splicing event that generates the NMD target isoform. Experiments performed have shown that rpL3 negatively neglects its expression by modulating the splicing event. Indeed, the over-expression of the protein in PC12 rat cells results in an increase in non-productive mRNA, which is the substrate of NMD, and a reduction in canonical mRNA. From these results, the rpL3 gene has been defined as a post-transcriptional type-feedback regulation model in which the protein regulates the splicing modes of its same gene: under normal growth conditions, canonical transcript is produced; instead, when cellular conditions result in excess protein, the expression of that messenger is inhibited and splicing proceeds mainly according to the alternative mode. The result of this event is an increase in levels of non-productive transcript, recognized and degraded by the surveillance mechanism, and consequent reduction in protein levels.