The Endoplasmic Reticulum Stress Response Factor CHOP-10 Protects against Hypoxia-induced Neuronal Death

Abstract

Hypoxia-induced gene expression is a critical determinant of neuron survival after stroke. Understanding the cell autonomous genetic program controlling adaptive and pathological transcription could have important therapeutic implications. To identify the factors that modulate delayed neuronal apoptosis after hypoxic injury, we developed an in vitro culture model that recapitulates these divergent responses and characterized the sequence of gene expression changes using microarrays. Hypoxia induced a disproportionate number of bZIP transcription factors and related targets involved in the endoplasmic reticulum stress response. Although the temporal and spatial aspects of ATF4 expression correlated with neuron loss, our results did not support the anticipated pathological role for delayed CHOP expression. Rather, CHOP deletion enhanced neuronal susceptibility to both hypoxic and thapsigargin-mediated injury and attenuated brain-derived neurotrophic factorinduced neuroprotection. Also, enforced expression of CHOP prior to the onset of hypoxia protected wild-type cultures against subsequent injury. Collectively, these findings indicate CHOP serves a more complex role in the neuronal response to hypoxic stress with involvement in both ischemic preconditioning and delayed neuroprotection.

Combined chemical–genetic approach identifies cytosolic HSP70 dependence in rhabdomyosarcoma

“…This scenario is similar to human epidermal growth factor receptor 2 (HER2) amplification in patients with breast cancer, in whom HER2 amplification predicts poor outcomes with conventional chemotherapy but superior outcomes with HER2-targeted therapy (39,40). Consistent with this notion, CHOP promotes cell survival or death in a context-specific manner (24,41). Overall, these findings reveal a potentially important dual and contextspecific role for CHOP in RMS pathogenesis and identify CHOP as a promising biomarker to guide the clinical development of cytosolic HSP70 inhibitors to treat RMS patients.…”

MKP-1 antagonizes C/EBP β activity and lowers the apoptotic threshold after ischemic injury

“…To define the early signaling events involved in this pathological response, we used expression microarrays and identified MKP-1 as a candidate modifier transcript expressed transiently within the first three hours of hypoxia. 14 To validate the observed dynamics of the MKP-1 expression, we harvested total RNA and protein from primary cortical cultures and analyzed MKP-1 expression by qPCR and western blotting (Figures 1a and b). Hypoxia transiently stimulated levels of MKP-1 message (1.0 ± 0.4 versus 3.9 ± 2.6, P ¼ o 0.01) and protein in primary neuronal cultures.…”

Adaptation to ER Stress as a Mechanism of Resistance of Melanoma to Treatment

“…Strikingly, while over-expression of CHOP does not confer sensitivity of melanoma cells to ER stress-induced apoptosis, inhibition of CHOP by siRNA resulted in low levels of apoptosis in the cells (Zhang, et al unpublished data). These results suggest that, instead inducing apoptosis, CHOP may have a pro-survival role in melanoma cells, as it does in neurons (Halterman, et al, 2010). How the biological function of CHOP is switched from pro-apoptotic to pro-survival in melanoma cells remains, however, to be elucidated.…”