From Endocytic Adaptor to Transcriptional Regulator

Abstract

Huntingtin interacting protein 1 (HIP1), an adaptor protein involved in clathrin-dependent endocytosis that binds the polyglutamine repeat-containing protein huntingtin, is overexpressed in some prostate cancers. Noting that the androgen receptor (AR) also contains polyglutamine repeats, Mills et al. investigated possible interactions between HIP1 and the AR. Treatment of an AR-expressing prostate cancer cell line (LNCaP) with androgen led to an increase in nuclear AR and redistribution of about 50% of cytoplasmic HIP1 to the nucleus. HIP1 and AR coimmunoprecipitated from LNCaP cells and, when expressed in COS7 cells, the two proteins interacted in a mammalian two-hybrid screen. Chromatin immunoprecipitation analysis showed that androgen stimulated the recruitment of HIP1 to the androgen response element (ARE) of the prostate-specific androgen (PSA) promoter. In COS7 cells transfected with AR and HIP1, HIP1 enhanced transcriptional activation in response to androgen stimulation. HIP1 knockdown with silencing RNA in LNCaP cells led to a decrease in PSA abundance as well as that of the AR. Whereas mRNA abundance for PSA was also decreased, the reduction in AR abundance appeared to depend on increased degradation. Mutational analysis indicated that disruption of HIP1's lipid-binding capacity, which led to loss of HIP1 from a clathrin-coated vesicle fraction, enhanced androgen-dependent stimulation of transcription by HIP1, whereas disruption of a HIP1 nuclear localization sequence inhibited it. Thus, HIP1 appears to play a role in regulating transcription, distinct from its role in endocytosis. Vecchi and Di Fiore comment on links between endocytic proteins and the nucleus and discuss the idea that HIP1 could act as a hub connecting heterogeneous processes. I. G. Mills, L. Gaughan, C. Robson, T. Ross, S. McCracken, J. Kelly, D. E. Neal, Huntingtin interacting protein 1 modulates the transcriptional activity of nuclear hormone receptors. J. Cell Biol. 170 , 191-200 (2005). [Abstract] [Full Text] M. Vecchi, P. P. Di Fiore, It's HIP to be a hub: New trends for old-fashioned proteins. J. Cell Biol. 170 , 169-171 (2005). [Abstract] [Full Text]