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Androgen Receptor Mutations Identified in Prostate Cancer and Androgen Insensitivity Syndrome Display Aberrant ART-27 Coactivator Function

Departments of Microbiology (W.L., T.D., M.J.G.), Urology (W.L., S.H., T.D., S.S.T., S.K.L., M.J.G.), and Pharmacology (S.K.L., T.C.), New York University Cancer Institute, New York University School of Medicine, New York, New York 10016; and Molsoft (C.N.C.), La Jolla, California 92037

Address all correspondence and requests for reprints to: Susan K. Logan or Michael J. Garabedian, New York University Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, New York 10016. E-mail for M.J.G.: garabm01{at}med.nyu.edu; E-mail for S.K.L.: logans02{at}med.nyu.edu.

The transcriptional activity of the androgen receptor (AR) is modulated by interactions with coregulatory molecules. It has been proposed that aberrant interactions between AR and its coregulators may contribute to diseases related to AR activity, such as prostate cancer and androgen insensitivity syndrome (AIS); however, evidence linking abnormal receptor-cofactor interactions to disease is scant. ART-27 is a recently identified AR N-terminal coactivator that is associated with AR-mediated growth inhibition. Here we analyze a number of naturally occurring AR mutations identified in prostate cancer and AIS for their ability to affect AR response to ART-27. Although the vast majority of AR mutations appeared capable of increased activation in response to ART-27, an AR mutation identified in prostate cancer (AR P340L) and AIS (AR E2K) show reduced transcriptional responses to ART-27, whereas their response to the p160 class of coactivators was not diminished. Relative to the wild-type receptor, less ART-27 protein associated with the AR E2K substitution, consistent with reduced transcriptional response. Surprisingly, more ART-27 associated with AR P340L, despite the fact that the mutation decreased transcriptional activation in response to ART-27. Our findings suggest that aberrant AR-coactivator association interferes with normal ART-27 coactivator function, resulting in suppression of AR activity, and may contribute to the pathogenesis of diseases related to alterations in AR activity, such as prostate cancer and AIS.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Coregulators:   ART-27  |  SRC-1  |  GRIP1

Ligands:   R1881

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