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Molecular and Cellular Biology, October 2007, p. 6972-6984, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00419-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Combinatorial Control of Signal-Induced Exon Repression by hnRNP L and PSF{triangledown} ,{dagger}

Alexis A. Melton, Jason Jackson, Jiarong Wang, and Kristen W. Lynch*

Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038

Received 10 March 2007/ Returned for modification 9 April 2007/ Accepted 20 July 2007

Cells can regulate their protein repertoire in response to extracellular stimuli via alternative splicing; however, the mechanisms controlling this process are poorly understood. The CD45 gene undergoes alternative splicing in response to T-cell activation to regulate T-cell function. The ESS1 splicing silencer in CD45 exon 4 confers basal exon skipping in resting T cells through the activity of hnRNP L and confers activation-induced exon skipping in T cells via previously unknown mechanisms. Here we have developed an in vitro splicing assay that recapitulates the signal-induced alternative splicing of CD45 and demonstrate that cellular stimulation leads to two changes to the ESS1-bound splicing regulatory complex. Activation-induced posttranslational modification of hnRNP L correlates with a modest increase in the protein's repressive activity. More importantly, the splicing factor PSF is recruited to the ESS1 complex in an activation-dependent manner and accounts for the majority of the signal-regulated ESS1 activity. The associations of hnRNP L and PSF with the ESS1 complex are largely independent of each other, but together these proteins account for the total signal-regulated change in CD45 splicing observed in vitro and in vivo. Such a combinatorial effect on splicing allows for precise regulation of signal-induced alternative splicing.

* Corresponding author. Mailing address: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038. Phone: (214) 648-2645. Fax: (214) 648-8856. E-mail: kristen.lynch{at}utsouthwestern.edu

{triangledown} Published ahead of print on 30 July 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, October 2007, p. 6972-6984, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00419-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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