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The RNA-binding and adaptor protein Sam68 modulates signal-dependent splicing and transcriptional activity of the androgen receptor

Lookup NU author(s): Dr Prabhakar Rajan, Dr Luke Gaughan, Caroline Dalgliesh, Dr Amira El-Sherif, Professor Craig Robson, Professor Hing Leung, Professor David Elliott

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Abstract

The RNA-binding protein Sam68 has been reported to be up-regulated in clinical cases of prostate cancer (PCa), where it is thought to contribute to cell proliferation and survival. Consistent with this, we observed over-expression of Sam68 in a panel of clinical prostate tumours as compared with benign controls. Since Sam68 is implicated in a number of signalling pathways, we reasoned that its role in PCa may involve modulation of the androgen receptor (AR) signalling cascade, which drives the onset and progression of PCa. We found that Sam68 interacts with the AR in vivo in LNCaP cells, and is dynamically recruited to androgen response elements within the promoter region of the prostate-specific antigen (PSA) gene. Based on its known functions and nuclear location, Sam68 might either: (a) co-regulate AR-dependent transcription positively or negatively; or (b) modulate AR-dependent alternative splicing by enhancing incorporation of a Sam68-responsive exon transcribed under the control of an androgen-responsive promoter. We tested these possibilities using functional assays. Both wild-type Sam68 protein and the Sam68V229F mutant, which is impaired in RNA binding, functioned as a ligand-dependent AR co-activator on an androgen-regulated reporter gene. In contrast, splicing of a Sam68-responsive variable exon, transcribed under control of an androgen-responsive promoter, was strongly repressed in the presence of AR and androgens. This splicing inhibition was reversed by ectopic expression of Sam68 but enhanced by Sam68V229F. These results demonstrate that Sam68 has separable effects on AR-regulated transcriptional activity and alternative splicing, both of which may affect PCa phenotypes. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Publication metadata

Author(s): Rajan P, Gaughan L, Dalgliesh C, El-Sherif A, Robson CN, Leung HY, Elliott DJ

Publication type: Article

Publication status: Published

Journal: Journal of Pathology

Year: 2008

Volume: 215

Issue: 1

Pages: 67-77

ISSN (print): 0022-3417

ISSN (electronic): 1096-9896

Publisher: John Wiley & Sons Ltd.

URL: http://dx.doi.org/10.1002/path.2324

DOI: 10.1002/path.2324

PubMed id: 18273831


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