title: Auto-activation of c-JUN gene by amino acid deprivation of hepatocellular carcinoma cells reveals a novel c-JUN-mediated signaling pathway.
abstract: Mammalian cells respond to protein or amino acid (AA) limitation by activating a number of signaling pathways, collectively referred to as the AA response (AAR), that modulate a range of cellular functions, including transcriptional induction of target genes. This study demonstrates that in hepatocellular carcinoma cells, expression of c-JUN, JUN-B, c-FOS, and FOS-B was induced by the AAR, whereas JUN-D, FRA-1, and FRA-2 were not. Of the four activated FOS/JUN members, c-JUN made the largest contribution to the induction of several known AAR target genes. For several human liver, prostate, and ovarian cell lines, the AAR-induced increase in c-JUN expression was greater in transformed cells compared with nontransformed counterparts, an effect independent of cell growth rate. Thus far, the best characterized AA-responsive genes are all transcriptionally activated by ATF4, but the AAR-dependent induction of c-JUN transcription was ATF4-independent. The increased expression of c-JUN was dependent on ATF2 and on activation of the MEK-ERK and JNK arms of the MAPK signaling pathways. Formation of c-JUN-ATF2-activated heterodimers was increased after AA limitation, and c-JUN or ATF2 knockdown suppressed the induction of c-JUN and other AAR target genes. AA deprivation triggers a feed-forward process that involves phosphorylation of existing c-JUN protein by JNK and subsequent auto-activation of the c-JUN gene by recruitment of c-JUN and ATF2 to two AP-1 sites within the proximal promoter. The results document the novel observation that AP-1 sequences within the c-JUN gene can function as transcriptional amino acid-response elements.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shands Cancer Center, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Lingchen
authors.initials: L
authors.lastname: Fu
authors.forename: Mukundh
authors.initials: M
authors.lastname: Balasubramanian
authors.forename: Jixiu
authors.initials: J
authors.lastname: Shan
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Dudenhausen
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kilberg
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism; D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D016762:Genes, fos / Q000235:genetics; D016758:Genes, jun; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D016759:Oncogene Protein p65(gag-jun) / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: C497105:ATF2 protein, human; C497109:ATF4 protein, human; D051698:Activating Transcription Factor 2; D000596:Amino Acids; D016759:Oncogene Protein p65(gag-jun); D051701:Activating Transcription Factor 4