title: MAPK signaling triggers transcriptional induction of cFOS during amino acid limitation of HepG2 cells.
abstract: Amino acid (AA) deprivation in mammalian cells activates a collection of signaling cascades known as the AA response (AAR), which is characterized by transcriptional induction of stress-related genes, including FBJ murine osteosarcoma viral oncogene homolog (cFOS). The present study established that the signaling mechanism underlying the AA-dependent transcriptional regulation of the cFOS gene in HepG2 human hepatocellular carcinoma cells is independent of the classic GCN2-eIF2-ATF4 pathway. Instead, a RAS-RAF-MEK-ERK cascade mediates AAR signaling to the cFOS gene. Increased cFOS transcription is observed from 4-24 h after AAR-activation, exhibiting little or no overlap with the rapid and transient increase triggered by the well-known serum response. Furthermore, serum is not required for the AA-responsiveness of the cFOS gene and no phosphorylation of promoter-bound serum response factor (SRF) is observed. The ERK-phosphorylated transcription factor E-twenty six-like (p-ELK1) is increased in its association with the cFOS promoter after activation of the AAR. This research identified cFOS as a target of the AAR and further highlights the importance of AA-responsive MAPK signaling in HepG2 cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 32610.
authors.forename: Jixiu
authors.initials: J
authors.lastname: Shan
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 32610.
authors.forename: William
authors.initials: W
authors.lastname: Donelan
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 32610.
authors.forename: Jaclyn N
authors.initials: JN
authors.lastname: Hayner
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 32610.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 32610.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Dudenhausen
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, Florida 32610. Electronic address: mkilberg@ufl.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kilberg
mesh_terms: D051701:Activating Transcription Factor 4 / Q000502:physiology; D000596:Amino Acids / Q000172:deficiency* / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016762:Genes, fos / Q000235:genetics*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C497109:ATF4 protein, human; D000596:Amino Acids; D051701:Activating Transcription Factor 4; C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: ATF4; GCN2; hepatocellular carcinoma; immediate early response genes; nutrient deprivation