Identification of novel stress-induced genes downstream of chop.
CHOP (GADD153) is a small nuclear protein that dimerizes avidly with members of the C/EBP family of transcription factors. Normally undetectable, it is expressed at high levels in cells exposed to conditions that perturb protein folding in the endoplasmic reticulum and induce an endoplasmic reticulum stress response. CHOP expression in stressed cells is linked to the development of programmed cell death and, in some instances, cellular regeneration. In this study, representational difference analysis was used to compare the complement of genes expressed in stressed wild-type mouse embryonic fibroblasts with those expressed in cells nullizygous for chop. CHOP expression, in concert with a second signal, was found to be absolutely required for the activation by stress of a set of previously undescribed genes referred to as DOCs (for downstream of CHOP). DOC4 is a mammalian ortholog of a Drosophila gene, Tenm/Odz, implicated in patterning of the early fly embryo, whereas DOC6 encodes a newly recognized homolog of the actin-binding proteins villin and gelsolin. These results reveal the existence of a novel CHOP-dependent signaling pathway, distinct from the known endoplasmic reticulum unfolded protein response, which may mediate changes in cell phenotype in response to stress.
Wang
X Z
XZ
Skirball Institute of Biomolecular Medicine, the Departments of Medicine, Cell Biology and the Kaplan Cancer Center, NYU Medical Center, New York, NY 10016, USA.
Kuroda
M
M
Sok
J
J
Batchvarova
N
N
Kimmel
R
R
Chung
P
P
Zinszner
H
H
Ron
D
D
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D000001:Calcimycin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D019281:Dimerization; D004721:Endoplasmic Reticulum / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D005786:Gene Expression Regulation; D008565:Membrane Proteins; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology
C113762:Avil protein, mouse; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; C113761:Tenm4 protein, mouse; D014157:Transcription Factors; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D000001:Calcimycin; D019284:Thapsigargin; D008741:Methyl Methanesulfonate