Premium
HuR inhibits apoptosis by amplifying Akt signaling through a positive feedback loop
Author(s) -
Singh Mamata,
Martinez Alaina R.,
Govindaraju Suman,
Lee Beth S.
Publication year - 2013
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24120
Subject(s) - apoptosis , protein kinase b , microbiology and biotechnology , positive feedback , pi3k/akt/mtor pathway , loop (graph theory) , feedback loop , signal transduction , chemistry , negative feedback , biology , cancer research , biochemistry , computer science , engineering , mathematics , electrical engineering , voltage , computer security , combinatorics
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. J. Cell. Physiol. 228: 182–189, 2013. © 2012 Wiley Periodicals, Inc.