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Molecular and Cellular Biology, September 2008, p. 5507-5516, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00530-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Repression of Prespliceosome Complex Formation at Two Distinct Steps by Fox-1/Fox-2 Proteins{triangledown} ,{dagger}

Hua-Lin Zhou1 and Hua Lou1,2,3*

Department of Genetics,1 Case Comprehensive Cancer Center,2 Center for RNA Molecular Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 441063

Received 1 April 2008/ Returned for modification 1 May 2008/ Accepted 13 June 2008

Precise and robust regulation of alternative splicing provides cells with an essential means of gene expression control. However, the mechanisms that ensure the tight control of tissue-specific alternative splicing are not well understood. It has been demonstrated that robust regulation often results from the contributions of multiple factors to one particular splicing pathway. We report here a novel strategy used by a single splicing regulator that blocks the formation of two distinct prespliceosome complexes to achieve efficient regulation. Fox-1/Fox-2 proteins, potent regulators of alternative splicing in the heart, skeletal muscle, and brain, repress calcitonin-specific splicing of the calcitonin/CGRP pre-mRNA. Using biochemical analysis, we found that Fox-1/Fox-2 proteins block prespliceosome complex formation at two distinct steps through binding to two functionally important UGCAUG elements. First, Fox-1/Fox-2 proteins bind to the intronic site to inhibit SF1-dependent E' complex formation. Second, these proteins bind to the exonic site to block the transition of E' complex that escaped the control of the intronic site to E complex. These studies provide evidence for the first example of regulated E' complex formation. The two-step repression of presplicing complexes by a single regulator provides a powerful and accurate regulatory strategy.

* Corresponding author. Mailing address: Department of Genetics, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106. Phone: (216) 368-6419. Fax: (216) 368-0491. E-mail: hxl47{at}case.edu

{triangledown} Published ahead of print on 23 June 2008.

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

Molecular and Cellular Biology, September 2008, p. 5507-5516, Vol. 28, No. 17
0270-7306/08/$08.00+0     doi:10.1128/MCB.00530-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Tang, Z. Z., Zheng, S., Nikolic, J., Black, D. L. (2009). Developmental Control of CaV1.2 L-Type Calcium Channel Splicing by Fox Proteins. Mol. Cell. Biol. 29: 4757-4765 [Abstract] [Full Text]  
  • Goo, Y.-H., Cooper, T. A. (2009). CUGBP2 directly interacts with U2 17S snRNP components and promotes U2 snRNA binding to cardiac troponin T pre-mRNA. Nucleic Acids Res 37: 4275-4286 [Abstract] [Full Text]  
  • Fukumura, K., Taniguchi, I., Sakamoto, H., Ohno, M., Inoue, K. (2009). U1-independent pre-mRNA splicing contributes to the regulation of alternative splicing. Nucleic Acids Res 37: 1907-1914 [Abstract] [Full Text]  


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