title: Extracellular signal-regulated kinase signaling regulates the opposing roles of JUN family transcription factors at ETS/AP-1 sites and in cell migration.
abstract: JUN transcription factors bind DNA as part of the AP-1 complex, regulate many cellular processes, and play a key role in oncogenesis. The three JUN proteins (c-JUN, JUNB, and JUND) can have both redundant and unique functions depending on the biological phenotype and cell type assayed. Mechanisms that allow this dynamic switching between overlapping and distinct functions are unclear. Here we demonstrate that JUND has a role in prostate cell migration that is the opposite of c-JUN's and JUNB's. RNA sequencing reveals that opposing regulation by c-JUN and JUND defines a subset of AP-1 target genes with cell migration roles. cis-regulatory elements for only this subset of targets were enriched for ETS factor binding, indicating a specificity mechanism. Interestingly, the function of c-JUN and JUND in prostate cell migration switched when we compared cells with an inactive versus an active RAS/extracellular signal-regulated kinase (ERK) signaling pathway. We show that this switch is due to phosphorylation and activation of JUND by ERK. Thus, the ETS/AP-1 sequence defines a unique gene expression program regulated by the relative levels of JUN proteins and RAS/ERK signaling. This work provides a rationale for how transcription factors can have distinct roles depending on the signaling status and the biological function in question.
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana, USA.
authors.forename: Nagarathinam
authors.initials: N
authors.lastname: Selvaraj
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana, USA.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Budka
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana, USA.
authors.forename: Mary W
authors.initials: MW
authors.lastname: Ferris
authors.affiliation: Department of Biology, Indiana University, Bloomington, Indiana, USA.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Plotnik
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana, USA pchollen@indiana.edu.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Hollenhorst
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D020014:K562 Cells; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: C559371:JunD protein, human; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins