H. Zinszner et al., CHOP IS IMPLICATED IN PROGRAMMED CELL-DEATH IN RESPONSE TO IMPAIRED FUNCTION OF THE ENDOPLASMIC-RETICULUM, Genes & development, 12(7), 1998, pp. 982-995
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.