The Biologic Functions Of An RNA Binding Protein ROD1

ROD1(Regulator of differentiation1) is highly expressed in megakaryocytic cells and specifically binding with poly(G) and poly(U). Reportedly, Nrdl which is the homologue gene to mammalian ROD1can block yeast differentiation by preventing conjugation, meiosis. The RNA binding proteins which contain RRM (RNA recognize motif) as ROD1are existed in Stress granules (SG). n response to various types of stress, eukaryote cell activates multiple mechanisms to adapt the environmental changes for survival. The temporal installation of protein translation is one of these mechanisms. Stress granules (SG) which pack lots of untranslated mRNAs rapidly appear as a critical regulator involved in cellular adaptive response. Here, in the first chapter, we have previously identified that ROD1participated in the assembling of SG. Furthermore, we demonstrated that ROD1could interact with human antigen R (HuR). In the structure analysis, we identified it was RRM3that contributed to the interaction with HuR and the formation of SG.In addition, since the mechanism underlying ROD1-mediated cells differentiation remains largely unknown, we showed that ROD1could regulate vascular endothelia growth factor (VEGFA) pre-mRNA splicing for the first time in chapter2. VEGFA is kown as a key cytokine that can promote angiogenesis and participate in a variety of physiological and pathological processes. In general, VEGFA gene consists of eight exons and seven introns with approximately14kilobases in length. As a result of alternative selection of the splicing sites, pre-messenger RNA (pre-mRNA) of VEGFA can be processed into two sister families of proteins, with the sequence variation normally occurs in the C-terminal region. Each family has multiple isoforms of different numbers of amino acids via alternative splicing inclusion of exons. The VEGFA isoforms VEGFA165and VEGFA121were reported to regulate endothelial differentiation through ERK1/2dependent pathway. Several reports had demonstrated that VEGFA was also able to regulate tumor cells differentiation. In the splicing modle built in MEF, we demonstrated ROD1could act as a splicing factor regulating VEGFA splicing, resulting in the isoform VEGFA117accumulation. Interestingly, overexpression of ROD1could inhibit Hela cells migration, while delection of ROD1enhanced it. We also demonstrated that ROD1regulated migration through p38/MAPK pathway induced by VEGFA.All together, we presume that ROD1influences not only differentiation via regulating VEGFA pre-message RNA alternative splicing, but also migration through p38/MAPK pathway induced by VEGFA in certain tumor cells. Undoubtedly, this study provides a new insight into the fuction of ROD1, and offers clues to further understanding the mechanism of how ROD1regulate differention, the effect of inhibiting VEGFA expression on mRNA level also makes ROD1to be a potential target for certain cancer therapy.