NDLI: The DNA Damage Response Pathway Regulates the Alternative Splicing of the Apoptotic Mediator Bcl-x

Content Provider	Journal of Biological Chemistry (JBC)
Author	Shkreta, Lulzim Michelle, Laetitia Toutant, Johanne Tremblay, Michel L. Chabot, Benoit
Abstract	Alternative splicing often produces effectors with opposite functions in apoptosis. Splicing decisions must therefore be tightly connected to stresses, stimuli, and pathways that control cell survival and cell growth. We have shown previously that PKC signaling prevents the production of proapoptotic Bcl-xS to favor the accumulation of the larger antiapoptotic Bcl-xL splice variant in 293 cells. Here we show that the genotoxic stress induced by oxaliplatin elicits an ATM-, CHK2-, and p53-dependent splicing switch that favors the production of the proapoptotic Bcl-xS variant. This DNA damage-induced splicing shift requires the activity of protein-tyrosine phosphatases. Interestingly, the ATM/CHK2/p53/tyrosine phosphatases pathway activated by oxaliplatin regulates Bcl-x splicing through the same regulatory sequence element (SB1) that receives signals from the PKC pathway. Convergence of the PKC and DNA damage signaling routes may control the abundance of a key splicing repressor because SB1-mediated repression is lost when protein synthesis is impaired but is rescued by blocking proteasome-mediated protein degradation. The SB1 splicing regulatory module therefore receives antagonistic signals from the PKC and the p53-dependent DNA damage response pathways to control the balance of pro- and antiapoptotic Bcl-x splice variants.
Related Links	http://www.jbc.org/content/286/1/331.abstract
Ending Page	340
Starting Page	331
Page Count	10
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	1
Volume Number	286
DOI	10.1074/jbc.M110.162644
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2011-01-07
Access Restriction	Open
Subject Keyword	Apoptosis DNA Damage P53 Phosphatase Proteasome Protein Synthesis RNA Splicing Signal Transduction Bcl-x Oxaliplatin RNA
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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