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Molecular and Cellular Biology, May 2004, p. 4174-4183, Vol. 24, No. 10
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.10.4174-4183.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Polypyrimidine Tract Binding Protein Modulates Efficiency of Polyadenylation

Pedro Castelo-Branco,1,2 Andre Furger,1,3 Matthew Wollerton,4 Christopher Smith,4 Alexandra Moreira,2 and Nick Proudfoot1*

Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, Genetics Unit,1 Cell Activation and Gene Expression Group, IBMC, Universidade do Porto, Porto, Portugal,2 Department of Biochemistry, University of Oxford, Oxford OX1 3QU,3 Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom4

Received 17 December 2003/ Returned for modification 8 January 2004/ Accepted 29 January 2004

Polypyrimidine tract binding protein (PTB) is a major hnRNP protein with multiple roles in mRNA metabolism, including regulation of alternative splicing and internal ribosome entry site-driven translation. We show here that a fourfold overexpression of PTB results in a 75% reduction of mRNA levels produced from transfected gene constructs with different polyadenylation signals (pA signals). This effect is due to the reduced efficiency of mRNA 3' end cleavage, and in vitro analysis reveals that PTB competes with CstF for recognition of the pA signal's pyrimidine-rich downstream sequence element. This may be analogous to its role in alternative splicing, where PTB competes with U2AF for binding to pyrimidine-rich intronic sequences. The pA signal of the C2 complement gene unusually possesses a PTB-dependent upstream sequence, so that knockdown of PTB expression by RNA interference reduces C2 mRNA expression even though PTB overexpression still inhibits polyadenylation. Consequently, we show that PTB can act as a regulator of mRNA expression through both its negative and positive effects on mRNA 3' end processing.

* Corresponding author. Mailing address: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom. Phone and fax: 44-1865 275566. E-mail: nicholas.proudfoot{at}path.ox.ac.uk.

Molecular and Cellular Biology, May 2004, p. 4174-4183, Vol. 24, No. 10
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.10.4174-4183.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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