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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Cell Line
  • ELAV Proteins / genetics
  • ELAV Proteins / metabolism*
  • Feedback, Physiological / physiology*
  • GRB10 Adaptor Protein / genetics
  • GRB10 Adaptor Protein / metabolism
  • Gene Expression Regulation / physiology
  • Humans
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / metabolism
  • NF-kappa B
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Polymerase Chain Reaction
  • Protein Array Analysis
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA Interference
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction / physiology*
  • Swine


  • ELAV Proteins
  • GRB10 protein, human
  • NF-kappa B
  • RNA, Messenger
  • GRB10 Adaptor Protein
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt