microRNAs in the control of lymphocytes response.
[Tesi di dottorato]
Recently, it has become evident the importance of miRNAs in regulating immune response, as well as immune cell development. During my phD fellow I focused my attention on the relationship B-lymphocytes-microRNA; in particular I examined two the different topics: the microRNA activation in response to oncogenic virus infection and cloning of new microRNA within IBTK gene located in the genomic sequence 6q14.1, which is a hot spot of chromosomal rearrangements in lymphoproliferative disorders. Epstein–Barr virus (EBV), which infects over 90% of the adults, appears to have evolved to exploit the normal biology of B-cell development in order to persist as a life-long asymptomatic infection. Of the genes expressed during viral latency in EBV-associated diseases, LMP1 is the one most implicated in tumor formation. miR-155 plays a critical role in lymphocyte activation in vivo. and is induced by a variety of immune cell stimuli, i.e. toll-like receptor (TLR) ligands, TNF-α, interferon-beta (IFN-β) and antigens [B-cell receptor (BCR) engagement]. Here we show that LMP1 upregulates the expression of miR-155 mainly by activating the NF-κB pathway, which suggests that miR-155 can cooperate in the EBV-mediated transformation of B cells. I. Quinto and G. Scala have recently characterized the Inhibitor of Bruton’s tyrosine kinase (IBtk) gene (accession number AL050333) that encodes three adaptor proteins in cell signalling. Consistently, the human IBTK gene is located in the genomic sequence 6q14.1, which is a hot spot of chromosomal rearrangements in lymphoproliferative disorders. In this study, we have addressed whether the IBTK gene might play a role in transcription regulation as source of miRNAs. By bioinformatics analysis, we identified four putative precursors of miRNA (pre-miR) encoded by three distinct introns and the 3’ un-translated region (3’UTR) of the IBTK gene. Of them, only the pre-miR-IBTK3 encoded by intron 26 occurred in vivo, and was the effective substrate of RNase III Dicer.
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