Crossregulation and Functional Redundancy Between the Splicing Regulator PTB and Its Paralogs NPTB and ROD1

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2007 Aug 7

PMID 17679092

Citations 185

Authors

Rachel Spellman

Miriam Llorian

Christopher W J Smith

Affiliations

Soon will be listed here.

Abstract

Among the targets of the repressive splicing regulator, polypyrimidine tract binding protein (PTB) is its own pre-mRNA, where PTB-induced exon 11 skipping produces an RNA substrate for nonsense-mediated decay (NMD). To identify additional PTB-regulated alternative splicing events, we used quantitative proteomic analysis of HeLa cells after knockdown of PTB. Apart from loss of PTB, the only change was upregulation of the neuronally restricted nPTB, resulting from decreased skipping of nPTB exon 10, a splicing event that leads to NMD of nPTB mRNA. Compared with knockdown of PTB alone, simultaneous knockdown of PTB and nPTB led to larger changes in alternative splicing of known and newly identified PTB-regulated splicing events. Strikingly, the hematopoietic PTB paralog ROD1 also switched from a nonproductive splicing pathway upon PTB/nPTB knockdown. Our data indicate crossregulation between PTB and its paralogs via nonproductive alternative splicing and a large degree of functional overlap between PTB and nPTB.

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References

Lynch K . Consequences of regulated pre-mRNA splicing in the immune system. Nat Rev Immunol. 2004; 4(12):931-40. DOI: 10.1038/nri1497. View

Pan Q, Shai O, Misquitta C, Zhang W, Saltzman A, Mohammad N . Revealing global regulatory features of mammalian alternative splicing using a quantitative microarray platform. Mol Cell. 2004; 16(6):929-41. DOI: 10.1016/j.molcel.2004.12.004. View

Pautz A, Linker K, Hubrich T, Korhonen R, Altenhofer S, Kleinert H . The polypyrimidine tract-binding protein (PTB) is involved in the post-transcriptional regulation of human inducible nitric oxide synthase expression. J Biol Chem. 2006; 281(43):32294-302. DOI: 10.1074/jbc.M603915200. View

Sauliere J, Sureau A, Expert-Bezancon A, Marie J . The polypyrimidine tract binding protein (PTB) represses splicing of exon 6B from the beta-tropomyosin pre-mRNA by directly interfering with the binding of the U2AF65 subunit. Mol Cell Biol. 2006; 26(23):8755-69. PMC: 1636812. DOI: 10.1128/MCB.00893-06. View

Ule J, Stefani G, Mele A, Ruggiu M, Wang X, Taneri B . An RNA map predicting Nova-dependent splicing regulation. Nature. 2006; 444(7119):580-6. DOI: 10.1038/nature05304. View

Silva A, Pereira F, Morgado A, Kong J, Martins R, Faustino P . The canonical UPF1-dependent nonsense-mediated mRNA decay is inhibited in transcripts carrying a short open reading frame independent of sequence context. RNA. 2006; 12(12):2160-70. PMC: 1664719. DOI: 10.1261/rna.201406. View

Boutz P, Chawla G, Stoilov P, Black D . MicroRNAs regulate the expression of the alternative splicing factor nPTB during muscle development. Genes Dev. 2007; 21(1):71-84. PMC: 1759902. DOI: 10.1101/gad.1500707. View

Ni J, Grate L, Donohue J, Preston C, Nobida N, OBrien G . Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay. Genes Dev. 2007; 21(6):708-18. PMC: 1820944. DOI: 10.1101/gad.1525507. View

Lareau L, Inada M, Green R, Wengrod J, Brenner S . Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements. Nature. 2007; 446(7138):926-9. DOI: 10.1038/nature05676. View

10.

Boutz P, Stoilov P, Li Q, Lin C, Chawla G, Ostrow K . A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons. Genes Dev. 2007; 21(13):1636-52. PMC: 1899473. DOI: 10.1101/gad.1558107. View

11.

Rahman L, Bliskovski V, Reinhold W, Zajac-Kaye M . Alternative splicing of brain-specific PTB defines a tissue-specific isoform pattern that predicts distinct functional roles. Genomics. 2002; 80(3):245-9. DOI: 10.1006/geno.2002.6826. View

12.

Relogio A, Ben-Dov C, Baum M, Ruggiu M, Gemund C, Benes V . Alternative splicing microarrays reveal functional expression of neuron-specific regulators in Hodgkin lymphoma cells. J Biol Chem. 2004; 280(6):4779-84. DOI: 10.1074/jbc.M411976200. View

13.

Karp N, Griffin J, Lilley K . Application of partial least squares discriminant analysis to two-dimensional difference gel studies in expression proteomics. Proteomics. 2005; 5(1):81-90. DOI: 10.1002/pmic.200400881. View

14.

Perkins D, Pappin D, Creasy D, Cottrell J . Probability-based protein identification by searching sequence databases using mass spectrometry data. Electrophoresis. 1999; 20(18):3551-67. DOI: 10.1002/(SICI)1522-2683(19991201)20:18<3551::AID-ELPS3551>3.0.CO;2-2. View

15.

Polydorides A, Okano H, Yang Y, Stefani G, Darnell R . A brain-enriched polypyrimidine tract-binding protein antagonizes the ability of Nova to regulate neuron-specific alternative splicing. Proc Natl Acad Sci U S A. 2000; 97(12):6350-5. PMC: 18606. DOI: 10.1073/pnas.110128397. View

16.

Becskei A, Serrano L . Engineering stability in gene networks by autoregulation. Nature. 2000; 405(6786):590-3. DOI: 10.1038/35014651. View

17.

Graveley B . Sorting out the complexity of SR protein functions. RNA. 2000; 6(9):1197-211. PMC: 1369994. DOI: 10.1017/s1355838200000960. View

18.

Markovtsov V, Nikolic J, Goldman J, Turck C, Chou M, Black D . Cooperative assembly of an hnRNP complex induced by a tissue-specific homolog of polypyrimidine tract binding protein. Mol Cell Biol. 2000; 20(20):7463-79. PMC: 86300. DOI: 10.1128/MCB.20.20.7463-7479.2000. View

19.

Kikuchi T, Ichikawa M, Arai J, Tateiwa H, Fu L, Higuchi K . Molecular cloning and characterization of a new neuron-specific homologue of rat polypyrimidine tract binding protein. J Biochem. 2000; 128(5):811-21. DOI: 10.1093/oxfordjournals.jbchem.a022819. View

20.

Black D . Protein diversity from alternative splicing: a challenge for bioinformatics and post-genome biology. Cell. 2000; 103(3):367-70. DOI: 10.1016/s0092-8674(00)00128-8. View