PMID- 15130668
OWN - NLM
STAT- MEDLINE
DCOM- 20041005
LR  - 20240214
IS  - 0531-5565 (Print)
IS  - 0531-5565 (Linking)
VI  - 39
IP  - 5
DP  - 2004 May
TI  - Elevated gadd153/chop expression and enhanced c-Jun N-terminal protein kinase 
      activation sensitizes aged cells to ER stress.
PG  - 735-44
AB  - The endoplasmic reticulum (ER), as a processing plant for the folding and 
      posttranslational modification of proteins, is exquisitely sensitive to changes 
      in its internal environment. Various conditions, collectively termed 'ER stress', 
      can perturb ER functions, leading to the activation of a complex response known 
      as the unfolded protein response. Here, we investigated the response of 
      hepatocytes derived from young (4-5 months) and aged (24-26 months) rats to two 
      agents, thapsigargin (TG) and tunicamycin (TM), which act via different 
      mechanisms to induce ER stress. Old hepatocytes displayed greater cell death than 
      young cells following treatment with TG or TM, associated with higher expression 
      of the pro-apoptotic gene gadd153 (also known as chop) and enhanced c-Jun 
      N-terminal protein kinase (JNK) activation. Pharmacologic inhibition of JNK 
      decreased the expression of TG-stimulated gadd153 in old cells and reduced their 
      sensitivity to TG-induced cell death. Inhibition of p38, on the other hand, 
      enhanced TG-induced gadd153 expression and JNK activation, and augmented 
      TG-induced cell death. Additional experiments implicated the PERK/eIF-2 alpha 
      signaling pathway as a contributor to the higher Gadd153 expression and JNK 
      activation, and greater sensitivity of old cells to ER stress.
FAU - Li, Ji
AU  - Li J
AD  - Yale University School of Medicine, Department of Internal Medicine, Section of 
      Geriatrics, New Haven, CT 06511, USA.
FAU - Holbrook, Nikki J
AU  - Holbrook NJ
LA  - eng
GR  - T30-3489/PHS HHS/United States
GR  - T30AG21342/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Exp Gerontol
JT  - Experimental gerontology
JID - 0047061
RN  - 0 (CCAAT-Enhancer-Binding Proteins)
RN  - 0 (Ddit3 protein, rat)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Transcription Factors)
RN  - 11089-65-9 (Tunicamycin)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Aging/*physiology
MH  - Animals
MH  - Apoptosis/drug effects
MH  - CCAAT-Enhancer-Binding Proteins/*analysis/genetics
MH  - Cells, Cultured
MH  - Endoplasmic Reticulum/drug effects/*physiology
MH  - Enzyme Inhibitors/pharmacology
MH  - Gene Expression
MH  - Glycosylation/drug effects
MH  - Hepatocytes/*drug effects/physiology
MH  - JNK Mitogen-Activated Protein Kinases
MH  - Male
MH  - Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
MH  - Rats
MH  - Rats, Inbred F344
MH  - Thapsigargin/pharmacology
MH  - Transcription Factor CHOP
MH  - Transcription Factors/*analysis/genetics
MH  - Tunicamycin/pharmacology
MH  - p38 Mitogen-Activated Protein Kinases
EDAT- 2004/05/08 05:00
MHDA- 2004/10/06 09:00
CRDT- 2004/05/08 05:00
PHST- 2003/12/18 00:00 [received]
PHST- 2004/02/18 00:00 [revised]
PHST- 2004/02/19 00:00 [accepted]
PHST- 2004/05/08 05:00 [pubmed]
PHST- 2004/10/06 09:00 [medline]
PHST- 2004/05/08 05:00 [entrez]
AID - S0531556504000981 [pii]
AID - 10.1016/j.exger.2004.02.008 [doi]
PST - ppublish
SO  - Exp Gerontol. 2004 May;39(5):735-44. doi: 10.1016/j.exger.2004.02.008.