1. Remodelling of a polypyrimidine tract-binding protein complex during apoptosis activates cellular IRESs.
- Author
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King HA, Cobbold LC, Pichon X, Pöyry T, Wilson LA, Booden H, Jukes-Jones R, Cain K, Lilley KS, Bushell M, and Willis AE
- Subjects
- Cell Nucleus metabolism, Cyclin T genetics, Cyclin T metabolism, DNA-Binding Proteins, HeLa Cells, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Humans, MCF-7 Cells, Nuclear Matrix-Associated Proteins antagonists & inhibitors, Nuclear Matrix-Associated Proteins genetics, Nuclear Matrix-Associated Proteins metabolism, Octamer Transcription Factors antagonists & inhibitors, Octamer Transcription Factors genetics, Octamer Transcription Factors metabolism, PTB-Associated Splicing Factor, Polypyrimidine Tract-Binding Protein antagonists & inhibitors, Polypyrimidine Tract-Binding Protein genetics, RNA Interference, RNA, Messenger metabolism, RNA, Small Interfering metabolism, RNA-Binding Proteins antagonists & inhibitors, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, Y-Box-Binding Protein 1 metabolism, Apoptosis drug effects, Polypyrimidine Tract-Binding Protein metabolism, TNF-Related Apoptosis-Inducing Ligand pharmacology
- Abstract
Post-transcriptional control of gene expression is mediated by the interaction of RNA-binding proteins with their cognate mRNAs that specifically regulate their stability, localization and translation. mRNA-binding proteins are multifunctional and it has been proposed therefore that a combinatorial RNA-binding protein code exists that allows specific protein sub-complexes to control cytoplasmic gene expression under a range of pathophysiological conditions. We show that polypyrimidine tract-binding protein (PTB) is central to one such complex that forms in apoptotic cells. Thus, during apoptosis initiated by TNF-related apoptosis inducing ligand there is a change in the repertoire of RNA-binding proteins with which PTB interacts. We show that altering the cellular levels of PTB and its binding partners, either singly or in combination, is sufficient to directly change the rates of apoptosis with increased expression of PTB, YBX1, PSF and NONO/p54(nrb) accelerating this process. Mechanistically, we show that these proteins post-transcriptionally regulate gene expression, and therefore apoptotic rates, by interacting with and stimulating the activity of RNA elements (internal ribosome entry segments) found in mRNAs that are translated during apoptosis. Taken together, our data show that PTB function is controlled by a set of co-recruited proteins and importantly provide further evidence that it is possible to dictate cell fate by modulating cytoplasmic gene expression pathways alone.
- Published
- 2014
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