title: TAK1 inhibition accelerates cellular senescence of retinal pigment epithelial cells.
abstract: OBJECTIVE
  Oxidative stress and cellular senescence are known to contribute to the development of AMD; however, the mechanism is not fully understood. This study investigated the role of TGF-β-activated kinase 1 (TAK1) in the senescence of RPE cells as a model for the development of dry AMD.
  
  
  METHODS
  Cultured human RPE cells were treated with the TAK1 inhibitor 5Z-7-oxozeaenol for 1 hour, and then treated with 200 μM hydrogen peroxide for 1 hour. Human RPE cells that were not pretreated with TAK1 inhibitor for 1 hour served as controls. Senescence-associated β-galactosidase (SA-β-gal) activity was detected by histochemistry, and p53 expression by immunoblotting. Cell-cycle and apoptosis rate in RPE cells were determined by flow cytometry.
  
  
  RESULTS
  The TAK1 expression in human RPE cells was high and was altered on oxidative stress. Transforming growth factor-β-activated kinase 1 inhibition led to reduction in cell proliferation, cell-cycle arrest at G0/G1, and increased SA-β-gal expression, all known to be features of cell senescence. Exposure of cells to oxidative stress combined with inhibition of TAK1 activity decreased the expression of apoptotic proteins, such as p53, and promoted cellular senescence. Aberrant TAK1 activity in RPE cells triggered their secretion of factors that induced hypertrophy and fibrotic changes in neighboring cells.
  
  
  CONCLUSIONS
  The in vitro evidence indicated a role for TAK1 in the onset of senescence in RPE cells. The data shown hereby demonstrated that TAK1 activity is essential for maintaining normal function of RPE cells. Elucidation of its role in mechanisms underlying RPE cellular senescence induction may potentiate development of powerful tools for halting the development of dry AMD.
authors.affiliation: Kaplan Medical Center, affiliated with Hadassah-Hebrew University of Jerusalem, Rehovot, Israel.
authors.forename: Zeev
authors.initials: Z
authors.lastname: Dvashi
authors.affiliation: Kaplan Medical Center, affiliated with Hadassah-Hebrew University of Jerusalem, Rehovot, Israel.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Green
authors.affiliation: Kaplan Medical Center, affiliated with Hadassah-Hebrew University of Jerusalem, Rehovot, Israel.
authors.forename: Ayala
authors.initials: A
authors.lastname: Pollack
mesh_terms: D017209:Apoptosis / Q000502:physiology; D059447:Cell Cycle Checkpoints / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D057092:Geographic Atrophy / Q000503:physiopathology*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D018384:Oxidative Stress; D055213:Retinal Pigment Epithelium / Q000166:cytology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D004791:Enzyme Inhibitors; D020930:MAP Kinase Kinase Kinases; D016159:Tumor Suppressor Protein p53; D000099151:MAP Kinase Kinase Kinase 7
keywords: AMD; TAK1; oxidative stress; senescence