title: Regulation of phosphatase homologue of tensin protein expression by bone morphogenetic proteins in prostate epithelial cells.
abstract: BACKGROUND
  Phosphatase homologue of tensin (PTEN) is the most commonly mutated gene in prostate cancer. Bone morphogenetic proteins (BMPs) are known to promote differentiation and inhibit proliferation. Previously published reports from other organ systems led us to investigate a mechanistic relationship between PTEN and BMP signaling in prostate epithelial cells.
  
  
  METHODS
  We analyzed growth rate and PTEN expression in E6, BPH-1, and C4-2B prostate epithelial cells treated with BMP-4. We also treated doxacyclin-inducible PTEN-C4-2B cells with BMP-4 and doxacyclin to determine the effect of BMP on growth and PTEN expression in conditions of increasing PTEN expression. We determined the dependency of BMP-mediated growth inhibition via siRNA knockdown of PTEN expression and BMP treatment. We determined PTEN protein stability by determining the effect of BMP-4 on PTEN protein at time points after treatment with cyclohexamide, a translation inhibitor.
  
  
  RESULTS
  We found that BMP-4 induces PTEN in E6 and BPH-1 cells and reduces proliferation. Knockdown of PTEN attenuated the growth-inhibiting effects of BMP-4 in these cells. BMP-4 had no effect in PTEN-negative C4-2B cells, but doxacyclin-driven PTEN C4-2B cells responded to BMP-4 with enhanced PTEN and growth inhibition. BMP-4 also increased PTEN protein stability.
  
  
  CONCLUSIONS
  BMP signaling induces PTEN expression and sustains PTEN protein expression resulting in inhibition of prostate epithelial cell growth. These data are the first to identify a mechanistic linkage between BMP signaling and PTEN in the prostate, both of which are independently identified as tumor suppressors and suggest possible coordinate dysregulation in prostate cancer.
authors: Department of Pharmacology-Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA. tjjerde@iupui.edu
authors: Travis J
authors: TJ
authors: Jerde
authors: Zhong
authors: Z
authors: Wu
authors: Dan
authors: D
authors: Theodorescu
authors: Wade
authors: W
authors: Bushman
mesh_terms: D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis*; D011467:Prostate / Q000187:drug effects / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D055415:Bone Morphogenetic Protein 4; D034741:RNA, Small Interfering; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human