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Genes Dev. 2014 May 15;28(10):1068-84. doi: 10.1101/gad.237206.113. Epub 2014 May 1.

An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth.

Author information

  • 1Department of Pathology.
  • 2Department of Translational Oncology.
  • 3Department of Protein Chemistry.
  • 4Department of Molecular Biology.
  • 5Department of Biochemical and Cellular Pharmacology.
  • 6Department of Bioinformatics, Genentech, Inc., South San Francisco, California 94080, USA;
  • 7Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.

Abstract

The spliceosome machinery is composed of multimeric protein complexes that generate a diverse repertoire of mRNA through coordinated splicing of heteronuclear RNAs. While somatic mutations in spliceosome components have been discovered in several cancer types, the molecular bases and consequences of spliceosome aberrations in cancer are poorly understood. Here we report for the first time that PRPF6, a member of the tri-snRNP (small ribonucleoprotein) spliceosome complex, drives cancer proliferation by preferential splicing of genes associated with growth regulation. Inhibition of PRPF6 and other tri-snRNP complex proteins, but not other snRNP spliceosome complexes, selectively abrogated growth in cancer cells with high tri-snRNP levels. High-resolution transcriptome analyses revealed that reduced PRPF6 alters the constitutive and alternative splicing of a discrete number of genes, including an oncogenic isoform of the ZAK kinase. These findings implicate an essential role for PRPF6 in cancer via splicing of distinct growth-related gene products.

KEYWORDS:

PRPF6; RNAi; colon cancer; spliceosome; tri-snRNP

PMID:
24788092
PMCID:
PMC4035536
DOI:
10.1101/gad.237206.113
[PubMed - indexed for MEDLINE]
Free PMC Article
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