Document Detail


Pancreatic β-cells depend on basal expression of active ATF6α-p50 for cell survival even under nonstress conditions.
MedLine Citation:
PMID:  22189555     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Activating transcription factor 6 (ATF6) is one of three principle endoplasmic reticulum (ER) stress response proteins and becomes activated when ER homeostasis is perturbed. ATF6 functions to increase ER capacity by stimulating transcription of ER-resident chaperone genes such as GRP78. Using an antibody that recognizes active ATF6α-p50, we found that active ATF6α was detected in insulinoma cells and rodent islets even under basal conditions and the levels were further increased by ER stress. To examine the function of ATF6α-p50, we depleted endogenous ATF6α-p50 levels using small interfering RNA in insulinoma cells. Knockdown of endogenous ATF6α-p50 levels by ∼60% resulted in a reduction in the steady-state levels of GRP78 mRNA and protein levels in nonstressed cells. Furthermore, ATF6α knockdown resulted in an apoptotic phenotype. We hypothesized that removal of the ATF6α branch of the unfolded protein response (UPR) would result in ER stress. However, neither the PKR-like endoplasmic reticulum kinase (PERK), nor the inositol requiring enzyme 1 (IRE1) pathways of the UPR were significantly activated in ATF6α knockdown cells, although these cells were more sensitive to ER stress-inducing compounds. Interestingly, phosphorylation of JNK, p38, and c-Jun were elevated in ATF6α knockdown cells and inhibition of JNK or p38 kinases prevented apoptosis. These results suggest that ATF6α may have a role in maintaining β-cell survival even in the absence of ER stress.
Authors:
Tracy Teodoro; Tanya Odisho; Elena Sidorova; Allen Volchuk
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-12-21
Journal Detail:
Title:  American journal of physiology. Cell physiology     Volume:  302     ISSN:  1522-1563     ISO Abbreviation:  Am. J. Physiol., Cell Physiol.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-04-02     Completed Date:  2012-08-02     Revised Date:  2012-10-26    
Medline Journal Info:
Nlm Unique ID:  100901225     Medline TA:  Am J Physiol Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  C992-1003     Citation Subset:  IM    
Affiliation:
Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, ON, Canada.
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MeSH Terms
Descriptor/Qualifier:
Activating Transcription Factor 6 / genetics*,  metabolism*
Animals
Apoptosis / physiology
Cell Line, Tumor
Cell Survival / physiology
Cells, Cultured
Endoplasmic Reticulum / genetics,  metabolism
Gene Knockdown Techniques
HeLa Cells
Heat-Shock Proteins / genetics,  metabolism
Humans
Insulin-Secreting Cells / cytology*,  metabolism*
Insulinoma / genetics,  metabolism
Islets of Langerhans / metabolism
MAP Kinase Kinase 4 / genetics,  metabolism
Membrane Proteins / genetics,  metabolism
Mice
Phosphorylation
Protein-Serine-Threonine Kinases / genetics,  metabolism
Proto-Oncogene Proteins c-jun / genetics,  metabolism
RNA, Messenger / genetics
Rats
Signal Transduction
Unfolded Protein Response
eIF-2 Kinase / genetics,  metabolism
p38 Mitogen-Activated Protein Kinases / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
86641//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Activating Transcription Factor 6; 0/Atf6 protein, mouse; 0/Heat-Shock Proteins; 0/Membrane Proteins; 0/Proto-Oncogene Proteins c-jun; 0/RNA, Messenger; 0/molecular chaperone GRP78; EC 2.7.1.-/Ern2 protein, mouse; EC 2.7.1.-/Ern2 protein, rat; EC 2.7.10.-/PERK kinase; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/eIF-2 Kinase; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 2.7.12.2/MAP Kinase Kinase 4
Comments/Corrections
Comment In:
Am J Physiol Cell Physiol. 2012 Apr 1;302(7):C966-7   [PMID:  22237402 ]

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