PMID- 12021180
OWN - NLM
STAT- MEDLINE
DCOM- 20020618
LR  - 20131121
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 143
IP  - 6
DP  - 2002 Jun
TI  - Endoplasmic reticulum stress causes thyroglobulin retention in this organelle and 
      triggers activation of nuclear factor-kappa B via tumor necrosis factor 
      receptor-associated factor 2.
PG  - 2169-77
AB  - Perturbing the endoplasmic reticulum homeostasis of thyroid cell lines with 
      thapsigargin, a specific inhibitor of the sarcoendoplasmic reticulum Ca(2+) 
      adenosine triphosphatases, and tunicamycin, an inhibitor of the N-linked 
      glycosylation, blocked Tg in the endoplasmic reticulum. This event was signaled 
      outside the endoplasmic reticulum and resulted in activation of the c-Jun 
      N-terminal kinase (JNK)/stress-activated protein kinase and nuclear factor-kappa 
      B (NF-kappa B) stress response pathways. Activation of the JNK/stress-activated 
      protein kinase signaling pathway was assessed by measuring the amount of 
      phospho-JNK and the activity of JNK by kinase assays. Activation of the NF-kappa 
      B signaling pathway was assessed by measuring the level of inhibitory subunit I 
      kappa B alpha, DNA binding, and transcriptional activity of NF-kappa B. 
      Cycloheximide treatment, at a dose able to profoundly inhibit protein synthesis 
      in FRTL-5 cells, obliterated the decrease in the level of the inhibitory subunit 
      I kappa B alpha produced by thapsigargin and tunicamycin. Therefore, protein 
      synthesis was required to generate a signal from stressed endoplasmic reticulum. 
      This substantiates the hypothesis that endoplasmic reticulum retention of newly 
      synthesized Tg and other cargo (secretory and membrane) proteins functions 
      upstream of signal activation. Dominant negative TNF receptor-associated factor 2 
      (TRAF2) inhibited activation of NF-kappa B, which was also inhibited in embryonic 
      fibroblasts derived from TRAF2(-/-) mice, respect to their normal counterpart. 
      These data extend the recent demonstration that TRAF2 mediated JNK activation in 
      response to endoplasmic reticulum stress and strongly strengthened the idea that 
      endogenous stress signals initiated in the endoplasmic reticulum proceed by a 
      pathway similar to that initiated by plasma membrane receptors in response to 
      extracellular signals.
FAU - Leonardi, Antonio
AU  - Leonardi A
AD  - Dipartimento di Biologia e Patologia Cellulare e Molecolare, Federico II, 
      University of Naples, 80100 Naples, Italy.
FAU - Vito, Pasquale
AU  - Vito P
FAU - Mauro, Claudio
AU  - Mauro C
FAU - Pacifico, Francesco
AU  - Pacifico F
FAU - Ulianich, Luca
AU  - Ulianich L
FAU - Consiglio, Eduardo
AU  - Consiglio E
FAU - Formisano, Silvestro
AU  - Formisano S
FAU - Di Jeso, Bruno
AU  - Di Jeso B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (NF-kappa B)
RN  - 0 (Protein Synthesis Inhibitors)
RN  - 0 (Proteins)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 11089-65-9 (Tunicamycin)
RN  - 67526-95-8 (Thapsigargin)
RN  - 9010-34-8 (Thyroglobulin)
RN  - 98600C0908 (Cycloheximide)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 4)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Calcium/metabolism
MH  - Cells, Cultured
MH  - Cycloheximide/pharmacology
MH  - Electrophoresis
MH  - Endoplasmic Reticulum/drug effects/*physiology
MH  - Fibroblasts/metabolism
MH  - Genes, Reporter/genetics
MH  - *JNK Mitogen-Activated Protein Kinases
MH  - MAP Kinase Kinase 4
MH  - Mice
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - NF-kappa B/*metabolism
MH  - Precipitin Tests
MH  - Protein Synthesis Inhibitors/pharmacology
MH  - Proteins/*physiology
MH  - Signal Transduction/drug effects
MH  - Stress, Mechanical
MH  - TNF Receptor-Associated Factor 2
MH  - Thapsigargin/pharmacology
MH  - Thyroglobulin/*metabolism
MH  - Tunicamycin/pharmacology
EDAT- 2002/05/22 10:00
MHDA- 2002/06/19 10:01
CRDT- 2002/05/22 10:00
PHST- 2002/05/22 10:00 [pubmed]
PHST- 2002/06/19 10:01 [medline]
PHST- 2002/05/22 10:00 [entrez]
AID - 10.1210/endo.143.6.8825 [doi]
PST - ppublish
SO  - Endocrinology. 2002 Jun;143(6):2169-77. doi: 10.1210/endo.143.6.8825.