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J Cell Physiol. 2013 Jan;228(1):182-9. doi: 10.1002/jcp.24120.

HuR inhibits apoptosis by amplifying Akt signaling through a positive feedback loop.

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1
Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, Ohio, USA.

Abstract

Human antigen R (HuR) is a post-transcriptional regulator of gene expression that plays a key role in stabilizing mRNAs during cellular stress, leading to enhanced survival. HuR expression is tightly regulated through multiple transcription and post-transcriptional controls. Although HuR is known to stabilize a subset of mRNAs involved in cell survival, its role in the survival pathway of PI3-kinase/Akt signaling is unclear. Here, we show that in renal proximal tubule cells, HuR performs a central role in cell survival by amplifying Akt signaling in a positive feedback loop. Key to this feedback loop is HuR-mediated stabilization of mRNA encoding Grb10, an adaptor protein whose expression is critical for Akt activation. Stimulation of Akt by interaction with Grb10 then activates NF-κB, which further enhances HuR mRNA and protein expression. This feedback loop is active in unstressed cells, but its effects are increased during stress. Therefore, this study demonstrates a central role for HuR in Akt signaling and reveals a mechanism by which modest changes in HuR levels below or above normal may be amplified, potentially resulting in cell death or cellular transformation.

PMID:
22674407
PMCID:
PMC3443509
DOI:
10.1002/jcp.24120
[Indexed for MEDLINE]
Free PMC Article
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