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PTBP1-dependent regulation of USP5 alternative RNA splicing plays a role in glioblastoma tumorigenesis.
Mol Carcinog. 2012 Nov; 51(11):895-906.MC

Abstract

Aberrant RNA splicing is thought to play a key role in tumorigenesis. The assessment of its specific contributions is limited by the complexity of information derived from genome-wide array-based approaches. We describe how performing splicing factor-specific comparisons using both tumor and cell line data sets may more readily identify physiologically relevant tumor-specific splicing events. Affymetrix exon array data derived from glioblastoma (GBM) tumor samples with defined polypyrimidine tract-binding protein 1 (PTBP1) levels were compared with data from U251 GBM cells with and without PTBP1 knockdown. This comparison yielded overlapping gene sets that comprised only a minor fraction of each data set. The identification of a novel GBM-specific splicing event involving the USP5 gene led us to further examine its role in tumorigenesis. In GBM, USP5 generates a shorter isoform 2 through recognition of a 5' splice site within exon 15. Production of the USP5 isoform 2 was strongly correlated with PTBP1 expression in GBM tumor samples and cell lines. Splicing regulation was consistent with the presence of an intronic PTBP1 binding site and could be modulated through antisense targeting of the isoform 2 splice site to force expression of isoform 1 in GBM cells. The forced expression of USP5 isoform 1 in two GBM cell lines inhibited cell growth and migration, implying an important role for USP5 splicing in gliomagenesis. These results support a role for aberrant RNA splicing in tumorigenesis and suggest that changes in relatively few genes may be sufficient to drive the process.

Authors+Show Affiliations

Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21976412

Citation

Izaguirre, Daisy I., et al. "PTBP1-dependent Regulation of USP5 Alternative RNA Splicing Plays a Role in Glioblastoma Tumorigenesis." Molecular Carcinogenesis, vol. 51, no. 11, 2012, pp. 895-906.
Izaguirre DI, Zhu W, Hai T, et al. PTBP1-dependent regulation of USP5 alternative RNA splicing plays a role in glioblastoma tumorigenesis. Mol Carcinog. 2012;51(11):895-906.
Izaguirre, D. I., Zhu, W., Hai, T., Cheung, H. C., Krahe, R., & Cote, G. J. (2012). PTBP1-dependent regulation of USP5 alternative RNA splicing plays a role in glioblastoma tumorigenesis. Molecular Carcinogenesis, 51(11), 895-906. https://doi.org/10.1002/mc.20859
Izaguirre DI, et al. PTBP1-dependent Regulation of USP5 Alternative RNA Splicing Plays a Role in Glioblastoma Tumorigenesis. Mol Carcinog. 2012;51(11):895-906. PubMed PMID: 21976412.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PTBP1-dependent regulation of USP5 alternative RNA splicing plays a role in glioblastoma tumorigenesis. AU - Izaguirre,Daisy I, AU - Zhu,Wen, AU - Hai,Tao, AU - Cheung,Hannah C, AU - Krahe,Ralf, AU - Cote,Gilbert J, Y1 - 2011/10/04/ PY - 2011/01/08/received PY - 2011/06/21/revised PY - 2011/09/08/accepted PY - 2011/10/7/entrez PY - 2011/10/7/pubmed PY - 2013/1/8/medline SP - 895 EP - 906 JF - Molecular carcinogenesis JO - Mol. Carcinog. VL - 51 IS - 11 N2 - Aberrant RNA splicing is thought to play a key role in tumorigenesis. The assessment of its specific contributions is limited by the complexity of information derived from genome-wide array-based approaches. We describe how performing splicing factor-specific comparisons using both tumor and cell line data sets may more readily identify physiologically relevant tumor-specific splicing events. Affymetrix exon array data derived from glioblastoma (GBM) tumor samples with defined polypyrimidine tract-binding protein 1 (PTBP1) levels were compared with data from U251 GBM cells with and without PTBP1 knockdown. This comparison yielded overlapping gene sets that comprised only a minor fraction of each data set. The identification of a novel GBM-specific splicing event involving the USP5 gene led us to further examine its role in tumorigenesis. In GBM, USP5 generates a shorter isoform 2 through recognition of a 5' splice site within exon 15. Production of the USP5 isoform 2 was strongly correlated with PTBP1 expression in GBM tumor samples and cell lines. Splicing regulation was consistent with the presence of an intronic PTBP1 binding site and could be modulated through antisense targeting of the isoform 2 splice site to force expression of isoform 1 in GBM cells. The forced expression of USP5 isoform 1 in two GBM cell lines inhibited cell growth and migration, implying an important role for USP5 splicing in gliomagenesis. These results support a role for aberrant RNA splicing in tumorigenesis and suggest that changes in relatively few genes may be sufficient to drive the process. SN - 1098-2744 UR - https://www.unboundmedicine.com/medline/citation/21976412/PTBP1_dependent_regulation_of_USP5_alternative_RNA_splicing_plays_a_role_in_glioblastoma_tumorigenesis_ L2 - https://doi.org/10.1002/mc.20859 DB - PRIME DP - Unbound Medicine ER -