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HEY1 Leu94Met gene polymorphism dramatically modifies its biological functions

Oncogene volume 29, pages 411–420 (2010)Cite this article

Abstract

The hairy/enhancer-of-split related with YRPW motif 1 (HEY1) is a member of the basic-helix-loop-helix-Orange (bHLH-O) family of transcriptional repressors that mediate Notch signaling. Several cancer-related pathways also regulate HEY1 expression, and HEY1 itself acts as an indirect positive regulator of the p53 tumor suppressor protein and a negative regulator of androgen receptor activity. In this study we show how a naturally occurring non-synonymous polymorphism at codon 94 of HEY1, which results in a substitution of leucine by methionine (Leu94Met), converts HEY1 from an androgen receptor corepressor to an androgen receptor co-activator without affecting its intrinsic transcriptional repressive domains. The polymorphism Leu94Met also abolishes HEY1-mediated activation of p53 and suppresses the ability of HEY1 to induce p53-dependent cell-cycle arrest and aberrant cell differentiation in human osteosarcoma U2OS cells. Moreover, expression of HEY1, but not of the variant Leu94Met, confers sensitivity to p53-activating chemotherapeutic drugs on U2OS cells. In addition, we have identified motifs in HEY1 that are critical for the regulation of its subcellular localization and analysed how mutations in those motifs affect both HEY1 and HEY1-Leu94Met functions. These findings suggest that the polymorphism Leu94Met in HEY1 radically alters its biological activities and may affect oncogenic processes.

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Acknowledgements

We thank Ana Aranda for her continuous support and Linn Markert for technical assistance. This study was supported by the MICINN (SAF2007-62642, SAF2006-07785), the Fundación de Investigación Médica Mutua Madrileña, the FIS (RD06/0020/0036), the CRESCENDO (FP-018652) and Cancer Research UK (C11509/A8570).

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Authors and Affiliations

  1. Department of Cancer Biology, Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain

    M A Villaronga & B Belandia

  2. Department of Oncology, Androgen Signalling Laboratory, Imperial College London, Hammersmith Hospital, London, UK

    D N Lavery & C L Bevan

  3. Tumor Suppression Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    S Llanos

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  1. M A Villaronga
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  2. D N Lavery
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  3. C L Bevan
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  4. S Llanos
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  5. B Belandia
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Corresponding authors

Correspondence to S Llanos or B Belandia.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Villaronga, M., Lavery, D., Bevan, C. et al. HEY1 Leu94Met gene polymorphism dramatically modifies its biological functions. Oncogene 29, 411–420 (2010). https://doi.org/10.1038/onc.2009.309

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