Adaptor to nucleus

Adaptor proteins that mediate membrane trafficking have been implicated in cancers as signaling regulators; some are overexpressed in cancers, including prostate cancer. On page 191, Mills et al. provide an unexpected explanation for these observations. They find that the adaptor protein HIP1 moves to the nucleus following androgen stimulation, where it enhances transcription from androgen-responsive genes.Previous work showed that overexpression of HIP1 in prostate cancer cells correlates with recurrence, but how HIP1 might affect androgen receptor function was unknown. Now, Mills et al. measure the amount of HIP1 and androgen receptor protein in the nuclei of tissue culture cells before and after androgen stimulation. As expected, most of the androgen receptor moved to the nucleus. So did 50% of the HIP1 protein.

The two proteins copurified by immunoprecipitation and both purified with androgen-responsive promoter elements in ChIP assays, though it was not clear whether HIP1 contacted the DNA directly. Increasing the amount of HIP1 protein increased expression of an androgen-responsive reporter gene upon androgen stimulation. Similar transcriptional increases were detected with HIP1 overexpression and hormonal stimulation of estrogen and glucocorticoid receptors.

Although other adaptor proteins have been found in the nucleus this is only the second reported to translocate to the nucleus in response to ligand treatment. (The other is APPL.) And while signaling cascades from the cell surface to the nucleus are well-known, this newly uncovered function of HIP1 reveals a much more direct mechanism by which proteins near the cell surface can alter transcription.