Novel genetic and epigenetic alterations in ... - Ous-research.no
Novel genetic and epigenetic alterations in ... - Ous-research.no Novel genetic and epigenetic alterations in ... - Ous-research.no
Previous studies have shown that RCC2 (also known as TD-60) is associated with thesegregation of chromosomes in metaphase.[34] Indeed, RCC2 is critical for the integrationof kinetochores into the mitotic spindle, and may be required for overall spindleassembly.[35] siRNA suppression shows that RCC2 is absolutely required for progressionfrom prometaphase to metaphase and that its suppression activates the spindle assemblycheckpoint, hence creating an effective G2/M arrest, indefinitely blocking cells fromcompleting mitosis.[35] The same study also suggested that the presence of RCC2 is criticalfor the recruitment of other proteins involved in cell division to inner centromeres inmitosis, supported by a novel study which show that RCC2 is important for AURORA B (aprotein involved in the chromosomal passenger complex) localization, but not activity, andthat RCC2-depleted extracts were impaired in their ability to align chromosomes to themetaphase plate.[36]These findings support the assumption that mutation in RCC2 can be associated withimproved survival as cells with this mutation will be arrested before cell division if themutation causes transcriptional inactivation. The (A)10 repeat in RCC2 is located in exon 1which is in the 5’ untranslated region (UTR) of the gene, 76 bases upstream of the startcodon. UTRs are known to affect mRNA nuclear export, cytoplasmic localization andtranslational efficiency and stability.[37] The majority of translational control occurs at thelevel of initiation, thus implicating the 5’ UTR as a major site of translationalregulation.[38;39] It has also been shown that mononucleotide repeats in UTRs areconserved due to possible selective pressure relating to a functional role, and that theseconserved repeats are frequently altered in MSI-cancers, and so are speculated to be involvedin regulating gene expression.[40] Whether or not the indels seen in RCC2 arrest the cells22
entering M-phase remains to be seen, but the aforementioned studies combined with thepositive survival data seen here indicates that this might be the case.To summarize, by use of two independent tumor series we have showed that indels in RCC2divide the MSI subgroup into those with good and poor prognosis, and that this holds evenafter stratifying the tumors according to tumor stage.23
- Page 102 and 103: Journal of Translational Medicine 2
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- Page 108 and 109: BackgroundMost cases of colorectal
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- Page 133 and 134: INTRODUCTIONMicrosatellite instabil
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enter<strong>in</strong>g M-phase rema<strong>in</strong>s to be seen, but the aforementioned studies comb<strong>in</strong>ed with thepositive survival data seen here <strong>in</strong>dicates that this might be the case.To summarize, by use of two <strong>in</strong>dependent tumor series we have showed that <strong>in</strong>dels <strong>in</strong> RCC2divide the MSI subgroup <strong>in</strong>to those with good <strong>and</strong> poor prog<strong>no</strong>sis, <strong>and</strong> that this holds evenafter stratify<strong>in</strong>g the tumors accord<strong>in</strong>g to tumor stage.23