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Concentration-dependent control of pyruvate kinase M mutually exclusive splicing by hnRNP proteins.
Nat Struct Mol Biol. 2012 Feb 05; 19(3):346-54.NS

Abstract

Expression of the mammalian pyruvate kinase M (PKM) gene provides an important example of mutually exclusive splicing. We showed previously that the hnRNP proteins A1, A2 and PTB have a crucial role in this process. Here we provide evidence that concentration-dependent interactions involving a network of these proteins are sufficient to determine the outcome of PKM splicing. At high concentrations, such as those found in most cancer cells, hnRNPA1 binding to two sites in the upstream regulated exon (exon 9) orchestrates cooperative interactions leading to exon 9 exclusion. At lower concentrations, binding shifts to downstream intronic sites, such that exon 9 is included and exon 10 mainly excluded, with any mRNA including both exons degraded by nonsense-mediated decay. Together, our results provide a mechanism by which a few general factors control alternative splicing of a widely expressed transcript.

Authors+Show Affiliations

Department of Biological Sciences, Columbia University, New York, New York, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22307054

Citation

Chen, Mo, et al. "Concentration-dependent Control of Pyruvate Kinase M Mutually Exclusive Splicing By hnRNP Proteins." Nature Structural & Molecular Biology, vol. 19, no. 3, 2012, pp. 346-54.
Chen M, David CJ, Manley JL. Concentration-dependent control of pyruvate kinase M mutually exclusive splicing by hnRNP proteins. Nat Struct Mol Biol. 2012;19(3):346-54.
Chen, M., David, C. J., & Manley, J. L. (2012). Concentration-dependent control of pyruvate kinase M mutually exclusive splicing by hnRNP proteins. Nature Structural & Molecular Biology, 19(3), 346-54. https://doi.org/10.1038/nsmb.2219
Chen M, David CJ, Manley JL. Concentration-dependent Control of Pyruvate Kinase M Mutually Exclusive Splicing By hnRNP Proteins. Nat Struct Mol Biol. 2012 Feb 5;19(3):346-54. PubMed PMID: 22307054.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Concentration-dependent control of pyruvate kinase M mutually exclusive splicing by hnRNP proteins. AU - Chen,Mo, AU - David,Charles J, AU - Manley,James L, Y1 - 2012/02/05/ PY - 2011/09/16/received PY - 2011/12/02/accepted PY - 2012/2/7/entrez PY - 2012/2/7/pubmed PY - 2012/4/21/medline SP - 346 EP - 54 JF - Nature structural & molecular biology JO - Nat. Struct. Mol. Biol. VL - 19 IS - 3 N2 - Expression of the mammalian pyruvate kinase M (PKM) gene provides an important example of mutually exclusive splicing. We showed previously that the hnRNP proteins A1, A2 and PTB have a crucial role in this process. Here we provide evidence that concentration-dependent interactions involving a network of these proteins are sufficient to determine the outcome of PKM splicing. At high concentrations, such as those found in most cancer cells, hnRNPA1 binding to two sites in the upstream regulated exon (exon 9) orchestrates cooperative interactions leading to exon 9 exclusion. At lower concentrations, binding shifts to downstream intronic sites, such that exon 9 is included and exon 10 mainly excluded, with any mRNA including both exons degraded by nonsense-mediated decay. Together, our results provide a mechanism by which a few general factors control alternative splicing of a widely expressed transcript. SN - 1545-9985 UR - https://www.unboundmedicine.com/medline/citation/22307054/Concentration_dependent_control_of_pyruvate_kinase_M_mutually_exclusive_splicing_by_hnRNP_proteins_ L2 - http://dx.doi.org/10.1038/nsmb.2219 DB - PRIME DP - Unbound Medicine ER -