title: TACE/ADAM-17 phosphorylation by PKC-epsilon mediates premalignant changes in tobacco smoke-exposed lung cells.
abstract: BACKGROUND
  Tobacco smoke predisposes humans and animals to develop lung tumors, but the molecular events responsible for this are poorly understood. We recently showed that signaling mechanisms triggered by smoke in lung cells could lead to the activation of a growth factor signaling pathway, thereby promoting hyperproliferation of lung epithelial cells. Hyperproliferation is considered a premalignant change in the lung, in that increased rates of DNA synthesis are associated with an increased number of DNA copying errors, events that are exacerbated in the presence of tobacco smoke carcinogens. Despite the existence of DNA repair mechanisms, a small percentage of these errors go unrepaired and can lead to tumorigenic mutations. The results of our previous study showed that an early event following smoke exposure was the generation of oxygen radicals through the activation of NADPH oxidase. Although it was clear that these radicals transduced signals through the epidermal growth factor receptor (EGFR), and that this was mediated by TACE-dependent cleavage of amphiregulin, it remained uncertain how oxygen radicals were able to activate TACE.
  
  
  RESULTS
  In the present study, we demonstrate for the first time that phosphorylation of TACE at serine/threonine residues by tobacco smoke induces amphiregulin release and EGFR activation. TACE phosphorylation is triggered in smoke-exposed lung cells by the ROS-induced activation of PKC through the action of SRC kinase. Furthermore, we identified PKCε as the PKC isoform involved in smoke-induced TACE activation and hyperproliferation of lung cells.
  
  
  CONCLUSIONS
  Our data elucidate new signaling paradigms by which tobacco smoke promotes TACE activation and hyperproliferation of lung cells.
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, United States of America. hassan.alaoui@ucsf.edu
authors.forename: Hassan
authors.initials: H
authors.lastname: Lemjabbar-Alaoui
authors.forename: Sukhvinder S
authors.initials: SS
authors.lastname: Sidhu
authors.forename: Aklilu
authors.initials: A
authors.lastname: Mengistab
authors.forename: Marianne
authors.initials: M
authors.lastname: Gallup
authors.forename: Carol
authors.initials: C
authors.lastname: Basbaum
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D001980:Bronchi / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008168:Lung / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology*; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D017382:Reactive Oxygen Species; D066246:ErbB Receptors; D019061:src-Family Kinases; D051744:Protein Kinase C-epsilon; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse