title: IFI16 induction by glucose restriction in human fibroblasts contributes to autophagy through activation of the ATM/AMPK/p53 pathway.
abstract: BACKGROUND
  Glucose restriction in cells increases the AMP/ATP ratio (energetic stress), which activates the AMPK/p53 pathway. Depending upon the energetic stress levels, cells undergo either autophagy or cell death. Given that the activated p53 induces the expression of IFI16 protein, we investigated the potential role of the IFI16 protein in glucose restriction-induced responses.
  
  
  RESULTS
  We found that glucose restriction or treatment of human diploid fibroblasts (HDFs) with the activators of the AMPK/p53 pathway induced the expression of IFI16 protein. The induced levels of IFI16 protein were associated with the induction of autophagy and reduced cell survival. Moreover, the increase in the IFI16 protein levels was dependent upon the expression of the functional ATM protein kinase. Importantly, the knockdown of the IFI16 expression in HDFs inhibited the activation of the ATM/AMPK/p53 pathway in response to glucose restriction and also increased the survival of HDFs.
  
  
  CONCLUSIONS
  Our observations demonstrate a role for the IFI16 protein in the energetic stress-induced regulation of autophagy and cell survival. Additionally, our findings also indicate that the loss of IFI16 expression, as found in certain cancers, may provide a survival advantage to cancer cells in microenvironments with low glucose levels.
authors.affiliation: Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Duan
authors.forename: Larissa
authors.initials: L
authors.lastname: Ponomareva
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Veeranki
authors.forename: Divaker
authors.initials: D
authors.lastname: Choubey
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D001343:Autophagy / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C076700:IFI16 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose