Publication Date:
2006-04-29
Description:
Accumulation of misfolded protein in the endoplasmic reticulum (ER) triggers an adaptive stress response-termed the unfolded protein response (UPR)-mediated by the ER transmembrane protein kinase and endoribonuclease inositol-requiring enzyme-1alpha (IRE1alpha). We investigated UPR signaling events in mice in the absence of the proapoptotic BCL-2 family members BAX and BAK [double knockout (DKO)]. DKO mice responded abnormally to tunicamycin-induced ER stress in the liver, with extensive tissue damage and decreased expression of the IRE1 substrate X-box-binding protein 1 and its target genes. ER-stressed DKO cells showed deficient IRE1alpha signaling. BAX and BAK formed a protein complex with the cytosolic domain of IRE1alpha that was essential for IRE1alpha activation. Thus, BAX and BAK function at the ER membrane to activate IRE1alpha signaling and to provide a physical link between members of the core apoptotic pathway and the UPR.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hetz, Claudio -- Bernasconi, Paula -- Fisher, Jill -- Lee, Ann-Hwee -- Bassik, Michael C -- Antonsson, Bruno -- Brandt, Gabriel S -- Iwakoshi, Neal N -- Schinzel, Anna -- Glimcher, Laurie H -- Korsmeyer, Stanley J -- CA100707/CA/NCI NIH HHS/ -- P01 AI56296/AI/NIAID NIH HHS/ -- P01 CA92625/CA/NCI NIH HHS/ -- R01 AI32412/AI/NIAID NIH HHS/ -- R37 CA50239/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2006 Apr 28;312(5773):572-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115, USA. chetz@hsph.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16645094" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
*Apoptosis
;
DNA-Binding Proteins/metabolism
;
Endoplasmic Reticulum/*metabolism/ultrastructure
;
Endoribonucleases/*metabolism
;
Gene Expression Regulation
;
Heat-Shock Proteins/metabolism
;
Humans
;
Kidney/cytology/drug effects/metabolism
;
Liver/cytology/drug effects/metabolism
;
Mice
;
Mice, Knockout
;
Mitochondria/metabolism
;
Molecular Chaperones/metabolism
;
Nuclear Proteins/metabolism
;
Phosphorylation
;
Protein Folding
;
Protein Structure, Tertiary
;
Protein-Serine-Threonine Kinases/*metabolism
;
Proto-Oncogene Proteins c-bcl-2/metabolism
;
Recombinant Proteins/metabolism
;
Signal Transduction
;
Transcription Factor CHOP/metabolism
;
Transcription Factors
;
Tunicamycin/pharmacology
;
bcl-2 Homologous Antagonist-Killer Protein/chemistry/genetics/*metabolism
;
bcl-2-Associated X Protein/genetics/*metabolism
;
eIF-2 Kinase/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink