TY - JOUR
T1 - Protein kinase RNA/FADD/caspase-8 pathway mediates the proapoptotic activity of the RNA-binding protein human antigen R (HuR)
AU - Von Roretz, Christopher
AU - Gallouzi, Imed Eddine
N1 - Generated from Scopus record by KAUST IRTS on 2022-09-13
PY - 2010/5/28
Y1 - 2010/5/28
N2 - The RNA-binding protein human antigen R (HuR) has been implicated in apoptosis in multiple ways. Several studies have shown that in response to a variety of stresses HuR promotes the expression of proapoptotic mRNAs, whereas others reported its regulatory effect on antiapoptotic messages. We recently showed that in response to severe stress, HuR is cleaved to generate two cleavage products (CPs), HuR-CP1 (24 kDa) and HuR-CP2 (8 kDa), by which it promotes apoptotic cell death. Here, we show that this cleavage event is dependent on protein kinase RNA (PKR). Surprisingly, although in response to the apoptotic inducer staurosporine PKR itself is not phosphorylated, PKR triggers the cleavage of HuR via its downstream effector FADD that in turn activates the caspase-8/caspase-3 pathway. This effect, however, does not require the phosphorylation of the eukaryotic translation initiation factor 2α. Additionally, we observed that these HuR-CPs are sufficient to trigger cell death in the absence of activation of the PKR pathway. Therefore, our results support a model whereby in response to lethal stress, PKR, without being phosphorylated, activates the FADD/caspase-8/caspase-3 pathway to trigger HuR cleavage, and the HuR-CPs are then capable of promoting apoptosis. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
AB - The RNA-binding protein human antigen R (HuR) has been implicated in apoptosis in multiple ways. Several studies have shown that in response to a variety of stresses HuR promotes the expression of proapoptotic mRNAs, whereas others reported its regulatory effect on antiapoptotic messages. We recently showed that in response to severe stress, HuR is cleaved to generate two cleavage products (CPs), HuR-CP1 (24 kDa) and HuR-CP2 (8 kDa), by which it promotes apoptotic cell death. Here, we show that this cleavage event is dependent on protein kinase RNA (PKR). Surprisingly, although in response to the apoptotic inducer staurosporine PKR itself is not phosphorylated, PKR triggers the cleavage of HuR via its downstream effector FADD that in turn activates the caspase-8/caspase-3 pathway. This effect, however, does not require the phosphorylation of the eukaryotic translation initiation factor 2α. Additionally, we observed that these HuR-CPs are sufficient to trigger cell death in the absence of activation of the PKR pathway. Therefore, our results support a model whereby in response to lethal stress, PKR, without being phosphorylated, activates the FADD/caspase-8/caspase-3 pathway to trigger HuR cleavage, and the HuR-CPs are then capable of promoting apoptosis. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
UR - https://linkinghub.elsevier.com/retrieve/pii/S0021925819356066
UR - http://www.scopus.com/inward/record.url?scp=77952750913&partnerID=8YFLogxK
U2 - 10.1074/jbc.M109.087320
DO - 10.1074/jbc.M109.087320
M3 - Article
SN - 0021-9258
VL - 285
SP - 16806
EP - 16813
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 22
ER -