title: DAP5 ameliorates cisplatin-induced apoptosis of renal tubular cells.
abstract: BACKGROUND
  Nephrotoxicity of cisplatin limits its clinical application. Cisplatin-induced acute renal tubular epithelial cell apoptosis is one of the major mechanisms of cisplatin nephrotoxicity. Here, the role and regulation of death-associated protein 5 (DAP5) in cisplatin-induced tubular cell apoptosis were investigated.
  
  
  METHODS
  After upregulation of DAP5 expression by plasmid transfection and downregulation of DAP5 expression by small interfering RNA in human kidney tubular epithelial cell line (HKC) cells, the degree of cell apoptosis was assessed by flow cytometric analysis. The expression of Bax and Bcl-2 proteins was detected by Western blot analysis. The relationship between the PI3K/Akt/mTOR signaling pathway and DAP5 was also evaluated.
  
  
  RESULTS
  During cisplatin-induced apoptosis in HKC cells, DAP5 underwent proteolytic fragmentation, yielding an 86-kDa species, DAP5/p86. Overexpression of DAP5/p97 and DAP5/p86 increased the translation of Bcl-2 and reduced the extent of cisplatin-induced apoptosis. Knockdown of DAP5 expression using small interfering RNA decreased the translation of Bcl-2 and increased the degree of apoptosis. Neither manipulation affected the expression of Bax. DAP5 expression was positively regulated by the PI3K/Akt/mTOR signaling pathway.
  
  
  CONCLUSIONS
  Collectively, the results from the present study revealed a new role for DAP5 in cisplatin-induced apoptosis: DAP5/p97 and DAP5/p86 enhanced the translation of the anti-apoptotic protein Bcl-2 and inhibited cisplatin-induced apoptosis. The PI3K/Akt/mTOR signaling pathway may positively regulate the expression of DAP5.
authors.affiliation: Department of Nephrology, State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, Beijing, PR China.
authors.forename: Jian-jun
authors.initials: JJ
authors.lastname: Gao
authors.forename: Guang-yan
authors.initials: GY
authors.lastname: Cai
authors.forename: Yi-chun
authors.initials: YC
authors.lastname: Ning
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.forename: Ju-rong
authors.initials: JR
authors.lastname: Yang
authors.forename: Dan
authors.initials: D
authors.lastname: Dong
authors.forename: Bo
authors.initials: B
authors.lastname: Fu
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Shao-yuan
authors.initials: SY
authors.lastname: Cui
authors.forename: Xiang-mei
authors.initials: XM
authors.lastname: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002945:Cisplatin / Q000494:pharmacology*; D039603:Eukaryotic Initiation Factor-4G / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D019254:Genes, bcl-2 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C491300:EIF4G2 protein, human; D039603:Eukaryotic Initiation Factor-4G; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D002945:Cisplatin