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Identification of cis-acting elements and splicing factors involved in the regulation of BIM Pre-mRNA splicing.
PLoS One. 2014; 9(4):e95210.Plos

Abstract

Aberrant changes in the expression of the pro-apoptotic protein, BCL-2-like 11 (BIM), can result in either impaired or excessive apoptosis, which can contribute to tumorigenesis and degenerative disorders, respectively. Altering BIM pre-mRNA splicing is an attractive approach to modulate apoptosis because BIM activity is partly determined by the alternative splicing of exons 3 or 4, whereby exon 3-containing transcripts are not apoptotic. Here we identified several cis-acting elements and splicing factors involved in BIM alternative splicing, as a step to better understand the regulation of BIM expression. We analyzed a recently discovered 2,903-bp deletion polymorphism within BIM intron 2 that biased splicing towards exon 3, and which also impaired BIM-dependent apoptosis. We found that this region harbors multiple redundant cis-acting elements that repress exon 3 inclusion. Furthermore, we have isolated a 23-nt intronic splicing silencer at the 3' end of the deletion that is important for excluding exon 3. We also show that PTBP1 and hnRNP C repress exon 3 inclusion, and that downregulation of PTBP1 inhibited BIM-mediated apoptosis. Collectively, these findings start building our understanding of the cis-acting elements and splicing factors that regulate BIM alternative splicing, and also suggest potential approaches to alter BIM splicing for therapeutic purposes.

Authors+Show Affiliations

Cancer and Stem Cell Biology Signature Research Programme, Duke-NUS Graduate Medical School, Singapore, Singapore.School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.Cancer and Stem Cell Biology Signature Research Programme, Duke-NUS Graduate Medical School, Singapore, Singapore; Department of Haematology, Singapore General Hospital, Singapore, Singapore; Department of Medical Oncology, National Cancer Centre, Singapore, Singapore; Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Chapel Hill, North Carolina, United States of America.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24743263

Citation

Juan, Wen Chun, et al. "Identification of Cis-acting Elements and Splicing Factors Involved in the Regulation of BIM Pre-mRNA Splicing." PloS One, vol. 9, no. 4, 2014, pp. e95210.
Juan WC, Roca X, Ong ST. Identification of cis-acting elements and splicing factors involved in the regulation of BIM Pre-mRNA splicing. PLoS ONE. 2014;9(4):e95210.
Juan, W. C., Roca, X., & Ong, S. T. (2014). Identification of cis-acting elements and splicing factors involved in the regulation of BIM Pre-mRNA splicing. PloS One, 9(4), e95210. https://doi.org/10.1371/journal.pone.0095210
Juan WC, Roca X, Ong ST. Identification of Cis-acting Elements and Splicing Factors Involved in the Regulation of BIM Pre-mRNA Splicing. PLoS ONE. 2014;9(4):e95210. PubMed PMID: 24743263.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of cis-acting elements and splicing factors involved in the regulation of BIM Pre-mRNA splicing. AU - Juan,Wen Chun, AU - Roca,Xavier, AU - Ong,S Tiong, Y1 - 2014/04/17/ PY - 2014/02/19/received PY - 2014/03/25/accepted PY - 2014/4/19/entrez PY - 2014/4/20/pubmed PY - 2014/12/31/medline SP - e95210 EP - e95210 JF - PloS one JO - PLoS ONE VL - 9 IS - 4 N2 - Aberrant changes in the expression of the pro-apoptotic protein, BCL-2-like 11 (BIM), can result in either impaired or excessive apoptosis, which can contribute to tumorigenesis and degenerative disorders, respectively. Altering BIM pre-mRNA splicing is an attractive approach to modulate apoptosis because BIM activity is partly determined by the alternative splicing of exons 3 or 4, whereby exon 3-containing transcripts are not apoptotic. Here we identified several cis-acting elements and splicing factors involved in BIM alternative splicing, as a step to better understand the regulation of BIM expression. We analyzed a recently discovered 2,903-bp deletion polymorphism within BIM intron 2 that biased splicing towards exon 3, and which also impaired BIM-dependent apoptosis. We found that this region harbors multiple redundant cis-acting elements that repress exon 3 inclusion. Furthermore, we have isolated a 23-nt intronic splicing silencer at the 3' end of the deletion that is important for excluding exon 3. We also show that PTBP1 and hnRNP C repress exon 3 inclusion, and that downregulation of PTBP1 inhibited BIM-mediated apoptosis. Collectively, these findings start building our understanding of the cis-acting elements and splicing factors that regulate BIM alternative splicing, and also suggest potential approaches to alter BIM splicing for therapeutic purposes. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/24743263/Identification_of_cis_acting_elements_and_splicing_factors_involved_in_the_regulation_of_BIM_Pre_mRNA_splicing_ DB - PRIME DP - Unbound Medicine ER -