Identification of REPS2 as a putative modulator of NF-kappaB activity in prostate cancer cells.
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-kappaB 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-kappaB activity. This might involve loss of REPS2-p65 interaction, which would lead to increased NF-kappaB activity. Androgen-deprivation causes apoptosis of prostate cancer cells, and activated NF-kappaB 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.
Penninkhof
Fred
F
Department of Reproduction and Development, Erasmus MC, Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
Grootegoed
J Anton
JA
Blok
Leen J
LJ
D000818:Animals; D019556:COS Cells; D002135:Calcium-Binding Proteins; D002522:Chlorocebus aethiops; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000201:enzymology*; D011506:Proteins / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D014364:Tryptophan / Q000502:physiology
D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011506:Proteins; C489722:REPS2 protein, human; D051996:Transcription Factor RelA; D014364:Tryptophan; D013755:Tetradecanoylphorbol Acetate