CHOP IS IMPLICATED IN PROGRAMMED CELL-DEATH IN RESPONSE TO IMPAIRED FUNCTION OF THE ENDOPLASMIC-RETICULUM

Cellular stress, particularly in response to toxic and metabolic insul ts 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 exami ned in a murine deficiency model obtained by homologous recombination at the chop gene. Compared with the wild type, mouse embryonic fibrobl asts (MEFs) derived from chop -/- animals exhibited significantly less programmed cell death when challenged with agents that perturb ER fun ction. A similar deficit in programmed cells death in response to ER s tress was also observed in MEFs that lack CHOP's major dimerization pa rtner, C/EBP beta, implicating the CHOP-C/EBP pathway in programmed ce ll death. An animal model for studying the effects of chop on the resp onse to ER stress was developed. It entailed exposing mice with define d chop genotypes to a single sublethal intraperitoneal injection of tu nicamycin 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 condit ion known as acute tubular necrosis, a process that resolved by cellul ar regeneration. In the chop -/- animals, in spite of the severe impai rment 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 ce lls (a marker for programmed cell death), and significantly less evide nce for subsequent regeneration. CHOP therefore has a role in the indu ction of cell death under conditions associated with malfunction of th e ER and may also have a role in cellular regeneration under such circ umstances.