Title: PO-0239 A Mystery Of Infectology : Brain Abscess In A Cgd Patient
Abstract:<h3>ABSTRACT</h3> <i>MDM2</i> is an oncogene and critical negative regulator of tumor suppressor p53. Genotoxic stress causes alternative splicing of <i>MDM2</i> transcripts, which leads to alteration...<h3>ABSTRACT</h3> <i>MDM2</i> is an oncogene and critical negative regulator of tumor suppressor p53. Genotoxic stress causes alternative splicing of <i>MDM2</i> transcripts, which leads to alterations in p53 activity and contributes to tumorigenesis. <i>MDM2-ALT1</i> is one of transcripts predominantly produced in response to genotoxic stress and is comprised of terminal coding exons 3 and 12. Previously, we found that SRSF1 induces <i>MDM2-ALT1</i> by promoting <i>MDM2</i> exon 11 skipping. Here we report that splicing regulator SRSF2 antagonizes the regulation of SRSF1 by facilitating the inclusion of exon 11 through binding at two conserved exonic splicing enhancers. Overexpression of SRSF2 reduced the generation of <i>MDM2-ALT1</i> in genotoxic stress condition, whereas knockdown induces the expression of <i>MDM2-ALT1</i> in absence of genotoxic stress. Consistently, blocking the exon 11 SRSF2 binding sites using oligonucleotides promotes <i>MDM2-ALT1</i>. The regulation of MDM2 splicing by SRSF2 is also conserved in mouse as mutation of one SRSF2 binding site in <i>Mdm2</i> exon 11, using CRISPR-Cas9, increases the expression <i>MDM2-ALT1</i> homolog <i>Mdm2-MS2</i> and proliferation of NIH 3T3 cells. Taken together, these findings underscore the relevance of <i>MDM2</i> alternative splicing in cancer and suggest that p53 levels can be modulated by artificially regulating <i>MDM2</i> splicing.Read More