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      CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum

      , , , , , , ,
      Genes & Development
      Cold Spring Harbor Laboratory

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          Abstract

          Cellular stress, particularly in response to toxic and metabolic insults that perturb function of the endoplasmic reticulum (ER stress), is a powerful inducer of the transcription factor CHOP. The role of CHOP in the response of cells to injury associated with ER stress was examined in a murine deficiency model obtained by homologous recombination at the chop gene. Compared with the wild type, mouse embryonic fibroblasts (MEFs) derived from chop -/- animals exhibited significantly less programmed cell death when challenged with agents that perturb ER function. A similar deficit in programmed cells death in response to ER stress was also observed in MEFs that lack CHOP's major dimerization partner, C/EBPbeta, implicating the CHOP-C/EBP pathway in programmed cell death. An animal model for studying the effects of chop on the response to ER stress was developed. It entailed exposing mice with defined chop genotypes to a single sublethal intraperitoneal injection of tunicamycin and resulted in a severe illness characterized by transient renal insufficiency. In chop +/+ and chop +/- mice this was associated with the early expression of CHOP in the proximal tubules followed by the development of a histological picture similar to the human condition known as acute tubular necrosis, a process that resolved by cellular regeneration. In the chop -/- animals, in spite of the severe impairment in renal function, evidence of cellular death in the kidney was reduced compared with the wild type. The proximal tubule epithelium of chop -/- animals exhibited fourfold lower levels of TUNEL-positive cells (a marker for programmed cell death), and significantly less evidence for subsequent regeneration. CHOP therefore has a role in the induction of cell death under conditions associated with malfunction of the ER and may also have a role in cellular regeneration under such circumstances.

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          Author and article information

          Journal
          Genes & Development
          Genes & Development
          Cold Spring Harbor Laboratory
          0890-9369
          April 01 1998
          April 01 1998
          : 12
          : 7
          : 982-995
          Article
          10.1101/gad.12.7.982
          316680
          9531536
          057b830b-0afa-461a-b50e-917a9372df8a
          © 1998
          History

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