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Hey1, a Mediator of Notch Signaling, Is an Androgen Receptor Corepressor

Institute of Reproductive and Developmental Biology,¹ Department of Histopathology, Division of Investigative Science, Faculty of Medicine,³ Prostate Cancer Research Group, Department of Cancer Medicine, Imperial College London, London, United Kingdom²

Received 18 August 2004/ Returned for modification 14 September 2004/ Accepted 29 November 2004

Hey1 is a member of the basic helix-loop-helix-Orange family of transcriptional repressors that mediate Notch signaling. Here we show that transcription from androgen-dependent target genes is inhibited by Hey1 and that expression of a constitutively active form of Notch is capable of repressing transactivation by the endogenous androgen receptor (AR). Our results indicate that Hey1 functions as a corepressor for AF1 in the AR, providing a mechanism for cross talk between Notch and androgen-signaling pathways. Hey1 colocalizes with AR in the epithelia of patients with benign prostatic hyperplasia, where it is found in both the cytoplasm and the nucleus. In marked contrast, we demonstrate that Hey1 is excluded from the nucleus in most human prostate cancers, raising the possibility that an abnormal Hey1 subcellular distribution may have a role in the aberrant hormonal responses observed in prostate cancer.

* Corresponding author. Present address for Borja Belandia: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28029 Madrid, Spain. Phone: 34 91 585 4453. Fax: 34 91 585 4401. E-mail: bbelandia{at}iib.uam.es. Mailing address for Malcolm G. Parker: Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College, London, United Kingdom. Phone: 44 207 594 2177. Fax: 44 207 594 2184. E-mail: m.parker{at}imperial.ac.uk.

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