PI3K-Akt inactivation induced CHOP expression in endoplasmic reticulum-stressed cells

Abstract

Stress signals that impair the function of the endoplasmic reticulum (ER) can lead to an accumulation of unfolded proteins in the ER causing cell death. Recent studies have indicated that ER stress contributes to several diseases such as neurodegenerative disorders or diabetes. In the present study, we found that Akt down-regulation is important for inducing CHOP expression, an ER stress-induced transcription factor. Treatment with tunicamycin or thapsigargin, ER stress inducers, caused dephosphorylation of Akt from 12 to 24 h and induced cell death. Interestingly, treatment with a PI3K inhibitor alone induced CHOP expression and caused cell death.However, a MEK1 inhibitor induced neither CHOP expression nor cell death. These results indicate that the inactivation of Akt by ER stress induces CHOP expression and causes cell death. Therefore, Akt plays an important role in ER stressed condition and may have important implications for understanding ER stress-related diseases.

Involvement of Ca2+-mediated apoptotic signals in palmitate-induced MIN6N8a beta cell death

“…Our finding that palmitate-induced Ca 2+ influx and subsequent [Ca 2+ ] i elevation might affect ER stress response is in accord with a presumption that breakdown of [Ca 2+ ] i homeostasis is a critical modulator of ER stress response (Xu et al, 2005). Based on a recent report that Akt inactivation in thapsigargin-treated cells induces CHOP expression (Hyoda et al, 2006), we can hypothesize that palmitate-induced Ca 2+ influx reduces Akt signals and that this reduction may up-regulate CHOP expression.…”

Palmitate modulates intracellular signaling, induces endoplasmic reticulum stress, and causes apoptosis in mouse 3T3-L1 and rat primary preadipocytes

“…Recent studies demonstrated that exogenous fatty acids, especially palmitate, cause ER stress, associated with increased expression of the proapoptotic transcription factor CHOP and inactivation of Akt (5,23,24,39). As a self-protection mechanism, molecular chaperone GRP78 is upregulated, which is also often considered a molecular marker for ER stress.…”

P58IPKinhibits coxsackievirus-induced apoptosis via the PI3K/Akt pathway requiring activation of ATF6a and subsequent upregulation of mitofusin 2

“…Price et al demonstrated PI3K-mediated signalling pathway promotes chondrocyte survival from ER stress but it does not depend on ERK1/2 activation (Price et al, 2010). Similar reports on the involvement of PI3K/Akt pathway in regulating cell's survival-death decisions in ER stress conditions have been documented (Hyoda et al, 2006;Hosoi et al, 2007). All above reports are studies on UPR induced by pharmacological agents and have not provided data on the relationship between activation of survival pathway and expression of p58 IPK .…”