Dataset Information

IRS1 deficiency protects ?-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation.

ABSTRACT: Endoplasmic reticulum (ER) stress is among several pathological features that underlie ?-cell failure in the development of type 1 and type 2 diabetes. Adaptor proteins in the insulin/insulin-like-growth factor-1 signaling pathways, such as insulin receptor substrate-1 (IRS1) and IRS2, differentially impact ?-cell survival but the underlying mechanisms remain unclear. Here we report that ?-cells deficient in IRS1 (IRS1KO) are resistant, while IRS2 deficiency (IRS2KO) makes them susceptible to ER stress-mediated apoptosis. IRS1KOs exhibited low nuclear accumulation of spliced XBP-1 due to its poor stability, in contrast to elevated accumulation in IRS2KO. The reduced nuclear accumulation in IRS1KO was due to protein instability of Xbp1 secondary to proteasomal degradation. IRS1KO also demonstrated an attenuation in their general translation status in response to ER stress revealed by polyribosomal profiling. Phosphorylation of eEF2 was dramatically increased in IRS1KO enabling the ?-cells to adapt to ER stress by blocking translation. Furthermore, significantly high ER calcium (Ca(2+)) was detected in IRS1KO ?-cells even upon induction of ER stress. These observations suggest that IRS1 could be a therapeutic target for ?-cell protection against ER stress-mediated cell death by modulating XBP-1 stability, protein synthesis, and Ca(2+) storage in the ER.

SUBMITTER: Takatani T

PROVIDER: S-EPMC4932502 | biostudies-other | 2016 Jul

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation.

Takatani Tomozumi T Shirakawa Jun J Roe Michael W MW Leech Colin A CA Maier Bernhard F BF Mirmira Raghavendra G RG Kulkarni Rohit N RN

Scientific reports 20160705

Endoplasmic reticulum (ER) stress is among several pathological features that underlie β-cell failure in the development of type 1 and type 2 diabetes. Adaptor proteins in the insulin/insulin-like-growth factor-1 signaling pathways, such as insulin receptor substrate-1 (IRS1) and IRS2, differentially impact β-cell survival but the underlying mechanisms remain unclear. Here we report that β-cells deficient in IRS1 (IRS1KO) are resistant, while IRS2 deficiency (IRS2KO) makes them susceptible to ER ...[more]

PMID: 27378176

Similar Datasets

Project description:The mammalian target of rapamycin (mTOR)/S6K1 signaling pathway controls cell growth and proliferation. To assess the importance of S6K1 in the balance between death and survival in the liver, we have generated immortalized hepatocyte cell lines from wild-type and S6K1-deficient (S6K1(-/-)) mice. In S6K1(-/-) hepatocytes, caspase-8 and the pro-apoptotic protein Bid were constitutively down-regulated as compared with wild-type. Moreover, S6K1(-/-) hepatocytes failed to respond to the apoptotic trigger of death receptor activation. Neither caspase-8 activation nor FLIP(L) degradation in response to tumor necrosis factor alpha (TNF-alpha) or anti-Fas antibody (Jo2) was observed in cells lacking S6K1. Downstream events such as Bid cleavage, cytochrome C release, caspase-3 activation, DNA laddering, as well as the percentage of apoptotic cells were attenuated as compared with wild-type. In addition, the anti-apoptotic protein Bclx(L) was down-regulated in TNF-alpha-treated or Jo2-treated wild-type hepatocytes, but this response was abolished in S6K1(-/-)cells. In vivo, S6K1-deficient mice were protected against concanavalin A-induced apoptosis. The withdrawal of growth factors strongly induced apoptosis in wild-type, but not in S6K1(-/-) hepatocytes. S6K1 deficiency did not decrease Bclx(L)/Bim ratio on serum withdrawal, thereby protecting cells from cytochrome C release and DNA fragmentation. At the molecular level, the lack of S6K1-mediated negative feedback decreased insulin receptor substrate-1 (IRS-1) serine phosphorylation, resulting in activation of survival pathways mediated by phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase (ERK). However, S6K1(-/-) hepatocytes underwent apoptosis on serum withdrawal in combination with phosphatidylinositol 3-kinase (PI3K) or ERK inhibitors.This finding might explain the mechanism of resistance to mTOR inhibitors in cancer treatments and strongly suggests that the inhibition of S6K1 could protect against acute liver failure and, in combination with inhibitors that abrogate the sustained activation of Akt and ERK, could improve the efficacy of hepatocarcinoma (HCC) treatment.

Dataset Information

IRS1 deficiency protects ?-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation.

Publications

IRS1 deficiency protects β-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets