TY - JOUR
T1 - Autoregulation of Polypyrimidine Tract Binding Protein by Alternative Splicing Leading to Nonsense-Mediated Decay
AU - Wollerton, Matthew C.
AU - Gooding, Clare
AU - Wagner, Eric J.
AU - Garcia-Blanco, Mariano A.
AU - Smith, Christopher W.J.
N1 - Funding Information:
We thank Gavin Roberts for the original EST analyses leading to identification of PTBtr splicing; Steven Brenner and Ed Green for access to unpublished information and for helpful discussions and comments on the manuscript; J. Mendel, J. Meyers, and H. Dietz for details of the Upf1 targeting siRNAs and for hUpf1/rent1 antibody; Juan Valcárcel, Doug Black, and Brigitte Jockusch for antibodies; Richard Jackson for UNR protein; and Lawrence Livermore National Laboratory for genomic clone F21817. E.J.W. acknowledges a DOD predoctoral fellowship. This work was supported by Wellcome Trust progamme grant 059879 (to C.W.J.S.).
PY - 2004/1/16
Y1 - 2004/1/16
N2 - Polypyrimdine tract binding protein (PTB) is a regulator of alternative splicing, mRNA 3′ end formation, mRNA stability and localization, and IRES-mediated translation. Transient overexpression of PTB can influence alternative splicing, sometimes resulting in nonphysiological splicing patterns. Here, we show that alternative skipping of PTB exon 11 leads to an mRNA that is removed by NMD and that this pathway consumes at least 20% of the PTB mRNA in HeLa cells. We also show that exon 11 skipping is itself promoted by PTB in a negative feedback loop. This autoregulation may serve both to prevent disruptively high levels of PTB expression and to restore nuclear levels when PTB is mobilized to the cytoplasm. Our findings suggest that alternative splicing can act not only to generate protein isoform diversity but also to quantitatively control gene expression and complement recent bioinformatic analyses, indicating a high prevalence of human alternative splicing leading to NMD.
AB - Polypyrimdine tract binding protein (PTB) is a regulator of alternative splicing, mRNA 3′ end formation, mRNA stability and localization, and IRES-mediated translation. Transient overexpression of PTB can influence alternative splicing, sometimes resulting in nonphysiological splicing patterns. Here, we show that alternative skipping of PTB exon 11 leads to an mRNA that is removed by NMD and that this pathway consumes at least 20% of the PTB mRNA in HeLa cells. We also show that exon 11 skipping is itself promoted by PTB in a negative feedback loop. This autoregulation may serve both to prevent disruptively high levels of PTB expression and to restore nuclear levels when PTB is mobilized to the cytoplasm. Our findings suggest that alternative splicing can act not only to generate protein isoform diversity but also to quantitatively control gene expression and complement recent bioinformatic analyses, indicating a high prevalence of human alternative splicing leading to NMD.
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U2 - 10.1016/S1097-2765(03)00502-1
DO - 10.1016/S1097-2765(03)00502-1
M3 - Article
C2 - 14731397
AN - SCOPUS:0346124413
SN - 1097-2765
VL - 13
SP - 91
EP - 100
JO - Molecular cell
JF - Molecular cell
IS - 1
ER -