title: Nuclear ferritin mediated regulation of JNK signaling in corneal epithelial cells.
abstract: Corneal epithelial (CE) cells are exposed to environmental insults (e.g., UV-irradiation), yet they suffer little damage. Our previous studies suggest that chicken CE cells have a novel form of protection involving having ferritin in a nuclear location where it can bind to DNA and sequester free iron. Here we describe another potential nuclear ferritin-mediated protective mechanism: the down-regulation of the JNK signaling pathway. The JNK pathway has been shown by others to promote apoptosis in response to cell damage and also to be activated in CE cell lines following exposure to UV radiation. Here we show in COS7 reporter cell lines that the expression of ferritin in a nuclear localization significantly down-regulates the JNK pathway (p = 5.7 × 10(-6)), but has no effect on the NFkB or the Erk pathways. In organ cultures of embryonic chicken corneas, we observed that inhibiting the synthesis of nuclear ferritin in CE cells, using the iron-chelating molecule deferoxamine, led to an increase in JNK signaling, as measured by phospho-JNK levels compared to CE cells with nuclear ferritin. Furthermore, the chemical inhibition of the JNK pathway using the molecule AS601245 decreased the production of nuclear ferritin. Taken together, these observations suggest that in CE cells a feedback-loop exists in which JNK signaling increases the production of nuclear ferritin and, in turn, nuclear ferritin decreases the activity of the JNK signaling pathway.
authors.affiliation: Integrative Physiology and Pathobiology Department, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA, United States. Electronic address: james.kubilus@tufts.edu.
authors.forename: James K
authors.initials: JK
authors.lastname: Kubilus
authors.affiliation: Integrative Physiology and Pathobiology Department, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA, United States.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Beazley
authors.affiliation: Integrative Physiology and Pathobiology Department, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Talbot
authors.affiliation: Integrative Physiology and Pathobiology Department, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA, United States.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Linsenmayer
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003315:Cornea / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D019573:Epithelium, Corneal / Q000166:cytology / Q000378:metabolism; D005293:Ferritins / Q000502:physiology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D023421:Models, Animal
chemical_list: D007502:Iron Chelating Agents; D005293:Ferritins; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Cell survival; Corneal epithelium; Ferritin; JNK; UV protection