Poster abstracts
Poster number 39 submitted by Matias Montes
The role of the nuclear matrix protein Matrin3 as a regulator of MDM2 alternative splicing
Matias Montes (MCDB, The Ohio State University), Aishwarya Jacob (Center for Childhood Cancer and Blood Diseases, Nationwide Childrens Hospital), Dawn Chandler (Center for Childhood Cancer and Blood Diseases, Nationwide Childrens Hospital)
Abstract:
MDM2, a well-known negative regulator of the tumor suppressor protein p53 undergoes complex alternative splicing. One of its spliced isoforms, MDM2-ALT1 comprised of exons 3 and 12, is highly expressed in several cancers such as lung carcinoma, liposarcoma or rhabdomyosarcoma, and its expression correlates with a poor disease prognosis. MDM2-ALT1 expression is also upregulated under conditions of cellular genotoxic stress. The way that MDM2 splicing is controlled is not well understood.
Both published and unpublished data from our lab indicate that the factors SRSF1 (ASF/SF1), SRSF2 (SC35), FUBP-1 and PTBP1 act as either positive or negative regulators of this process. Interestingly, PTBP1 (Polypyrimidine Tract Binding Protein 1) is commonly known as a repressor of exon inclusion, but our results show that, in case of MDM2 alternative splicing it acts a positive regulator. This factor has been shown to interact with the nuclear matrix protein Matrin3, a recently identified splicing factor. Interestingly Matrin3 has also been shown to be implicated in the DNA damage response induced by genotoxic stress. RNA affinity chromatography experiments coupled with mass spectrometry, indicate that Matrin3 binds to intronic regions of the MDM2 pre-mRNA, thus supporting the hypothesis. In this work we investigate the role of Matrin3 as regulator of MDM2 alternative splicing and its interaction with the splicing factor PTBP1 in said regulation. Elucidating the participation of this factor in the alternative splicing of MDM2 could bring us one step closer in understanding how this is regulated under genotoxic stress and eventually also in cancer such as rhabdomyosarcoma.
Keywords: Splicing, MDM2, Matrin3