HuR inhibits apoptosis by amplifying Akt signaling through a positive feedback loop.
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.
Department of Physiology and Cell Biology, The Ohio State University College of Medicine, Columbus, Ohio, USA.
Mamata
M
Singh
Alaina R
AR
Martinez
Suman
S
Govindaraju
Beth S
BS
Lee
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology*; D051383:GRB10 Adaptor Protein / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D040081:Protein Array Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013552:Swine
D051959:ELAV Proteins; C096358:GRB10 protein, human; D016328:NF-kappa B; D012333:RNA, Messenger; D051383:GRB10 Adaptor Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt