Functional Consequences for Apoptosis by Transcription Elongation Regulator 1 (TCERG1)-Mediated Bcl-x and Fas/CD95 Alternative Splicing

PLoS One. 2015 Oct 13;10(10):e0139812. doi: 10.1371/journal.pone.0139812. eCollection 2015.

Abstract

Here, we present evidence for a specific role of the splicing-related factor TCERG1 in regulating apoptosis in live cells by modulating the alternative splicing of the apoptotic genes Bcl-x and Fas. We show that TCERG1 modulates Bcl-x alternative splicing during apoptosis and its activity in Bcl-x alternative splicing correlates with the induction of apoptosis, as determined by assessing dead cells, sub-G1-phase cells, annexin-V binding, cell viability, and cleavage of caspase-3 and PARP-1. Furthermore, the effect of TCERG1 on apoptosis involved changes in mitochondrial membrane permeabilization. We also found that depletion of TCERG1 reduces the expression of the activated form of the pro-apoptotic mitochondrial membrane protein Bak, which remains inactive by heterodimerizing with Bcl-xL, preventing the initial step of cytochrome c release in Bak-mediated mitochondrial apoptosis. In addition, we provide evidence that TCERG1 also participates in the death receptor-mediated apoptosis pathway. Interestingly, TCERG1 also modulates Fas/CD95 alternative splicing. We propose that TCERG1 sensitizes a cell to apoptotic agents, thus promoting apoptosis by regulating the alternative splicing of both the Bcl-x and Fas/CD95 genes. Our findings may provide a new link between the control of alternative splicing and the molecular events leading to apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / physiology*
  • Apoptosis / physiology*
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Cytochromes c / genetics
  • Cytochromes c / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Jurkat Cells
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism
  • Transcriptional Elongation Factors / genetics
  • Transcriptional Elongation Factors / metabolism*
  • bcl-2 Homologous Antagonist-Killer Protein / genetics
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism*
  • fas Receptor / genetics
  • fas Receptor / metabolism*

Substances

  • BAK1 protein, human
  • BCL2L1 protein, human
  • FAS protein, human
  • TCERG1 protein, human
  • Transcriptional Elongation Factors
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-X Protein
  • fas Receptor
  • Cytochromes c
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • CASP3 protein, human
  • Caspase 3

Grant support

This work was supported by grants from the Spanish Ministry of Economy and Competitiveness [grant numbers BFU2011-24577 and BFU2014-54660-R] and the Andalusian Government [Excellence Projects CVI-4626/2009 and BIO-2515/2012] to CS; the Spanish Ministry of Economy and Competitiveness [grant number BFU2013-44660-R] and the Andalusian Government [Excellence Project CTS-6587] to CHM; the Spanish Ministry of Economy and Competitiveness [grant numbers SAF2013-44677-R and FIS PI12/00506], the SPANISH AIDS Research Network RD12/0017/0015 that is included in Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008-2011, Instituto de Salud Carlos III, European Region Development Fund, ERDF (FEDER) to MC and JA. MM was supported by a fellowship from the Spanish Ministry of Education (FPU program). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.