title: Remodelling of a polypyrimidine tract-binding protein complex during apoptosis activates cellular IRESs.
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.
authors.affiliation: Medical Research Council Toxicology Unit, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: H A
authors.initials: HA
authors.lastname: King
authors.forename: L C
authors.initials: LC
authors.lastname: Cobbold
authors.forename: X
authors.initials: X
authors.lastname: Pichon
authors.forename: T
authors.initials: T
authors.lastname: Pöyry
authors.forename: L A
authors.initials: LA
authors.lastname: Wilson
authors.forename: H
authors.initials: H
authors.lastname: Booden
authors.forename: R
authors.initials: R
authors.lastname: Jukes-Jones
authors.forename: K
authors.initials: K
authors.lastname: Cain
authors.forename: K S
authors.initials: KS
authors.lastname: Lilley
authors.forename: M
authors.initials: M
authors.lastname: Bushell
authors.forename: A E
authors.initials: AE
authors.lastname: Willis
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002467:Cell Nucleus / Q000378:metabolism; D056906:Cyclin T / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D034521:Nuclear Matrix-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050810:Octamer Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000072670:PTB-Associated Splicing Factor; D038941:Polypyrimidine Tract-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D051840:Y-Box-Binding Protein 1 / Q000378:metabolism
chemical_list: D056906:Cyclin T; D004268:DNA-Binding Proteins; C083214:NONO protein, human; D034521:Nuclear Matrix-Associated Proteins; D050810:Octamer Transcription Factors; D000072670:PTB-Associated Splicing Factor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D038941:Polypyrimidine Tract-Binding Protein; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human