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How is Herstatin, a tumor suppressor splice variant of the oncogene HER2, regulated?

Lookup NU author(s): Marco Silipo, Dr Hannah Gautrey, Swapna Satam, Professor Tom Lennard, Professor Alison Tyson-Capper


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© 2017 Taylor & Francis Group, LLC The human epidermal growth factor receptor 2 (HER2)/receptor tyrosine-protein kinasebB-2 (ERBB2) is overexpressed in 20–30% of breast tumors leading to faster growing and more aggressive tumors. Alternative splicing generates a functionally distinct HER2 variant called Herstatin, which is produced by the inclusion of intron 8. Herstatin acts as a tumor suppressor by effectively blocking HER2 activity and cell proliferation, while promoting apoptosis. In the present study we investigated HER2 pre-mRNA regulatory sequences and splicing factors which regulate the alternative splicing of Herstatin. A Herstatin minigene, comprising exon 8/intron 8/exon 9 of HER2 was generated and subsequent in vitro splicing assays revealed that RNA secondary structure and somatic mutations did not impact on inclusion of intron 8. However, using RNase-assisted RNA chromatography, followed by mass spectrometry, we identified six RNA-binding proteins (splicing factors) that bind to RNA sequences surrounding exon 8/intron 8 and intron 8/exon 9 boundaries; these included hnRNP I, H1, D, A2/B1 and hnRNPA1 plus the SR protein SRSF1. Specifically, overexpression of hnRNP A1 significantly increased retention of intron 8 resulting in higher levels of Herstatin in SKBR3 breast cancer cells whereas SRSF1 only had a marginal effect in decreasing Herstatin but increased exogenous HER2 levels under these experimental conditions. In conclusion, we have identified the first splicing factors and regulatory sequences that are involved in the production of Herstatin.

Publication metadata

Author(s): Silipo M, Gautrey H, Satam S, Lennard T, Tyson-Capper A

Publication type: Article

Publication status: Published

Journal: RNA Biology

Year: 2017

Volume: 14

Issue: 5

Pages: 536-543

Online publication date: 09/12/2016

Acceptance date: 27/11/2016

ISSN (print): 1547-6286

ISSN (electronic): 1555-8584

Publisher: Taylor and Francis


DOI: 10.1080/15476286.2016.1267074


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