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Transactivation of ErbB1 and ErbB2 receptors by angiotensin II in normal human prostate stromal cells
Author(s) -
Lin Jianqing,
Freeman Michael R.
Publication year - 2002
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.10160
Subject(s) - stromal cell , epidermal growth factor , receptor , angiotensin ii , endocrinology , transactivation , medicine , growth factor , biology , chemistry , microbiology and biotechnology , biochemistry , gene , transcription factor
BACKGROUND Heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) is synthesized primarily in the stromal compartment of the human prostate and may regulate stromal as well as epithelial cell growth and survival. The primary cognate HB‐EGF receptor, ErbB1, has been shown recently to be transactivated by G‐protein coupled receptors (GPCRs) through regulated proteolytic cleavage of the membrane‐bound, precursor form of HB‐EGF. Previous studies have demonstrated that human prostate tissue, especially tissue from benign prostatic hyperplasia (BPH), has high angiotensin converting enzyme activity, and a high density of angiotensin (Ang) receptors in periurethral stromal cells. Because the pressor peptide Ang II signals through GPCRs, we tested the possibility that Ang II could transactivate ErbB1/ErbB2 in human prostate stromal (hPS) cells. METHODS Primary and early passage hPS cells were used as an in vitro model. Cells were stimulated by recombinant HB‐EGF or Ang II and total cell lysates were harvested for immunoprecipitation and Western blot. Cell growth was measured by [ 3 H]thymidine incorporation assay and 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyl‐tetrazoliumbromide (MTT) assay. RESULTS Ang II receptors AT1 and AT2 were expressed in hPS cells. ErbB1 and ErbB2 receptors were activated by HB‐EGF. Furthermore, Ang II was able to transactivate both ErbB1 and ErbB2, and this transactivation activity could be abolished by pretreatment with [Glu‐52]‐diphtheria toxin/CRM197, a specific inhibitor of HB‐EGF bioactivity. Consistent with its transactivation activity, Ang II modestly promoted hPS cell growth and this effect was abolished by pretreatment with the ErbB1 antagonist AG1478. CONCLUSION These experiments suggest a regulatory role for Ang II in the prostate stroma and implicate the endogenous stromal growth factor HB‐EGF as a mediator of Ang II signaling in the prostate. Prostate 54: 1–7, 2003. © 2002 Wiley‐Liss, Inc.