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Heterogeneous ribonucleoprotein A1 is part of an exon-specific splice-silencing complex controlled by oncogenic
N Matter1, M Marx, S Weg-Remers
1Forschungszentrum Karlsruhe, Institut für Toxikologie und Genetik, and Universität Karlsruhe, Institut für Genetik, Postfach 3640, 76021 Karlsruhe, Germany.
Abstract:
Regulation of alternative pre-mRNA splicing, recognized as increasingly important in causing human disease, was studied using the CD44 gene, whose splice variants have been implicated in tumor progression. We identified heterogeneous ribonucleoprotein (hnRNP) A1 as a protein interacting in vitro and in vivo with regulatory splice elements in CD44 variant exon v5. Transient overexpression of hnRNP A1 prevented v5 exon inclusion, dependent on the exonic elements. HnRNP A1-dependent repression was exon-specific and could be relieved by coexpression of oncogenic forms of Ras and Cdc42. The results define hnRNP A1 as a decisive part of an oncogene-regulated splice-silencing complex, which can select between multiple alternatively spliced exons.
Insights
Heterogeneous ribonucleoprotein (hnRNP) A1 regulates alternative splicing of CD44 variant exon v5, impacting tumor progression. Oncogenes Ras and Cdc42 can relieve this repression, highlighting hnRNP A1
Area of Science:
- Molecular Biology
- RNA Splicing
- Cancer Biology
Background:
- Alternative pre-mRNA splicing is crucial in human diseases, including cancer.
- The CD44 gene exhibits splice variants linked to tumor progression.
- Understanding splicing regulation is key to targeting disease mechanisms.
Purpose of the Study:
- To investigate the role of heterogeneous ribonucleoprotein (hnRNP) A1 in CD44 alternative splicing.
- To identify proteins involved in the regulation of CD44 variant exon v5 inclusion.
- To elucidate the mechanism by which oncogenes modulate splicing complex activity.
Main Methods:
- In vitro and in vivo protein-interaction assays.
- Transient overexpression of hnRNP A1 in cellular models.
- Analysis of CD44 variant exon v5 inclusion.
- Coexpression studies with oncogenic Ras and Cdc42.
Main Results:
- hnRNP A1 directly interacts with regulatory elements in CD44 variant exon v5.
- Overexpression of hnRNP A1 represses v5 exon inclusion in an exonic element-dependent manner.
- Oncogenic Ras and Cdc42 can relieve hnRNP A1-mediated splicing repression.
- hnRNP A1 acts as an exon-specific splice-silencing factor.
Conclusions:
- hnRNP A1 is a key component of an oncogene-regulated splice-silencing complex.
- This complex selectively targets alternatively spliced exons, such as CD44 v5.
- The findings provide insights into cancer progression mechanisms driven by aberrant splicing.