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Inhibition of the PI 3‐kinase pathway disrupts the unfolded protein response and reduces sensitivity to ER stress‐dependent apoptosis
- Source :
- The FASEB Journal. 34:12521-12532
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
Abstract
- Class Ia phosphoinositide 3-kinases (PI3K) are critical mediators of insulin and growth factor action. We have demonstrated that the p85α regulatory subunit of PI3K modulates the unfolded protein response (UPR) by interacting with and regulating the nuclear translocation of XBP-1s, a transcription factor essential for the UPR. We now show that PI3K activity is required for full activation of the UPR. Pharmacological inhibition of PI3K in cells blunts the ER stress-dependent phosphorylation of IRE1α and PERK, decreases induction of ATF4, CHOP, and XBP-1 and upregulates UPR target genes. Cells expressing a human p85α mutant (R649W) previously shown to inhibit PI3K, exhibit decreased activation of IRE1α and PERK and reduced induction of CHOP and ATF4. Pharmacological inhibition of PI3K, overexpression of a mutant of p85α that lacks the ability to interact with the p110α catalytic subunit (∆p85α) or expression of mutant p85α (R649W) in vivo, decreased UPR-dependent induction of ER stress response genes. Acute tunicamycin treatment of R649W+/- mice revealed reduced induction of UPR target genes in adipose tissue, whereas chronic tunicamycin exposure caused sustained increases in UPR target genes in adipose tissue. Finally, R649W+/- cells exhibited a dramatic resistance to ER stress-dependent apoptosis. These data suggest that PI3K pathway dysfunction causes ER stress that may drive the pathogenesis of several diseases including Type 2 diabetes and various cancers.
- Subjects :
- Male
X-Box Binding Protein 1
0301 basic medicine
endocrine system
medicine.medical_treatment
Apoptosis
P110α
Biochemistry
Cell Line
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Genetics
medicine
Animals
Molecular Biology
Transcription factor
PI3K/AKT/mTOR pathway
Growth factor
ATF4
Tunicamycin
Endoplasmic Reticulum Stress
Cell biology
Class Ia Phosphatidylinositol 3-Kinase
Mice, Inbred C57BL
030104 developmental biology
Adipose Tissue
chemistry
Unfolded Protein Response
Unfolded protein response
Phosphorylation
030217 neurology & neurosurgery
Biotechnology
Subjects
Details
- ISSN :
- 15306860 and 08926638
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- The FASEB Journal
- Accession number :
- edsair.doi.dedup.....4e34dd72b44568ed642dfe5c0f629899