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Identification of REPS2 as a putative modulator of NF-κB activity in prostate cancer cells

Oncogene volume 23, pages 5607–5615 (2004)Cite this article

Abstract

The protein REPS2 is implicated in growth factor receptor-mediated endocytosis and signalling, and its expression is downregulated in androgen-independent prostate cancer cells. Herein, the NF-κB subunit p65 is identified as a human REPS2 protein partner, interacting with the EH domain of REPS2. Using crystal structure data from literature and experimental data from yeast and mammalian two-hybrid analysis, the results indicate that the NPF-motif in p65 acts as binding site for the EH domain in REPS2. However, in cultured prostate cancer cells, the REPS2–p65 interaction is triggered upon stimulation with phorbol ester (PMA). This indicates that PMA-sensitive signalling pathways can affect the interaction between REPS2 and p65. During prostate cancer progression from androgen-dependent to androgen-independent growth, downregulation of REPS2 is accompanied by upregulation of NF-κB activity. This might involve loss of REPS2–p65 interaction, which would lead to increased NF-κB activity. Androgen-deprivation causes apoptosis of prostate cancer cells, and activated NF-κB is a known inhibitor of apoptosis. Hence, decreased expression of REPS2 might be a key factor, causing prostate cancer cells to become resistant to induction of apoptosis by androgen deprivation.

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Acknowledgements

We thank Dr HJ Dubbink of the Department of Pathology and Dr GW Jenster of the Department of Urology, Josephine Nefkens Institute, Erasmus MC, Rotterdam, The Netherlands, for collaboration, constructs, comments and discussions. This work was supported by a grant from the Netherlands Organisation for Scientific Research (903-46-169) and by the Erasmus Trust Fund.

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  1. Department of Reproduction and Development, Erasmus MC, Rotterdam, PO Box 1738, Rotterdam, 3000 DR, The Netherlands

    Fred Penninkhof, J Anton Grootegoed & Leen J Blok

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  1. Fred Penninkhof
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Correspondence to Leen J Blok.

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Penninkhof, F., Grootegoed, J. & Blok, L. Identification of REPS2 as a putative modulator of NF-κB activity in prostate cancer cells. Oncogene 23, 5607–5615 (2004). https://doi.org/10.1038/sj.onc.1207750

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