Gene Set: MARCINIAK_ER_STRESS_RESPONSE_VIA_CHOP

Standard name MARCINIAK_ER_STRESS_RESPONSE_VIA_CHOP
Systematic name M1477
Brief description Endoplasmic retuculum (ER) stress response (caused by tunicamycin [PubChem=5282055]) genes dependent on CHOP [GeneID=13198].
Full description or abstract Unfolded and malfolded client proteins impose a stress on the endoplasmic reticulum (ER), which contributes to cell death in pathophysiological conditions. The transcription factor C/EBP homologous protein (CHOP) is activated by ER stress, and CHOP deletion protects against its lethal consequences. We find that CHOP directly activates GADD34, which promotes ER client protein biosynthesis by dephosphorylating phospho-Ser 51 of the alpha-subunit of translation initiation factor 2 (eIF2alpha) in stressed cells. Thus, impaired GADD34 expression reduces client protein load and ER stress in CHOP(-/-) cells exposed to perturbations that impair ER function. CHOP(-/-) and GADD34 mutant cells accumulate less high molecular weight protein complexes in their stressed ER than wild-type cells. Furthermore, mice lacking GADD34-directed eIF2alpha dephosphorylation, like CHOP(-/-) mice, are resistant to renal toxicity of the ER stress-inducing drug tunicamycin. CHOP also activates ERO1alpha, which encodes an ER oxidase. Consequently, the ER of stressed CHOP(-/-) cells is relatively hypo-oxidizing. Pharmacological and genetic manipulations that promote a hypo-oxidizing ER reduce abnormal high molecular weight protein complexes in the stressed ER and protect from the lethal consequences of ER stress. CHOP deletion thus protects cells from ER stress by decreasing ER client protein load and changing redox conditions within the organelle.
Collection C2: curated gene sets
      CGP: chemical and genetic perturbations
Source publication Pubmed 15601821   Authors: Marciniak SJ,Yun CY,Oyadomari S,Novoa I,Zhang Y,Jungreis R,Nagata K,Harding HP,Ron D
Exact source Table 1S
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Organism Mus musculus
Contributed by Kevin Vogelsang (MSigDB Team)
Source platform MOUSE_SEQ_ACCESSION
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Version history 3.1: First introduced

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