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¹ Cancer Research UK Uro-Oncology Research Group, Department of Oncology, University of Cambridge, Hutchison/Medical Research Council Cancer Research Centre, Cambridge CB2 2XZ, England, UK
² Prostate Research Group, Northern Institute for Cancer Research, University of Newcastle upon Tyne, Medical School, Newcastle upon Tyne NE2 4HH, England, UK
³ Department of Internal Medicine and Graduate Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI 48109

Correspondence to I.G. Mills: igm23{at}cam.ac.uk

Internalization of activated receptors regulates signaling, and endocytic adaptor proteins are well-characterized in clathrin-mediated uptake. One of these adaptor proteins, huntingtin interacting protein 1 (HIP1), induces cellular transformation and is overexpressed in some prostate cancers. We have discovered that HIP1 associates with the androgen receptor through a central coiled coil domain and is recruited to DNA response elements upon androgen stimulation. HIP1 is a novel androgen receptor regulator, significantly repressing transcription when knocked down using a silencing RNA approach and activating transcription when overexpressed. We have also identified a functional nuclear localization signal at the COOH terminus of HIP1, which contributes to the nuclear translocation of the protein. In conclusion, we have discovered that HIP1 is a nucleocytoplasmic protein capable of associating with membranes and DNA response elements and regulating transcription.

I.G. Mills and L. Gaughan contributed equally to this paper.

Abbreviations used in this paper: ANTH, AP180 NH₂-terminal homology; AR, androgen receptor; ARE, androgen response element; ChIP, chromatin immunoprecipitation; HIP1, huntingtin interacting protein 1; PSA, prostate-specific antigen; siRNA, silencing RNA.

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