title: A dominant-negative c-jun mutant inhibits lung carcinogenesis in mice.
abstract: Lung cancer is the leading cause of cancer mortality in the United States and worldwide. The identification of key regulatory and molecular mechanisms involved in lung tumorigenesis is therefore critical to increase our understanding of this disease and could ultimately lead to targeted therapies to improve prevention and treatment. Induction of members of the activator protein-1 (AP-1) transcription factor family has been described in human non-small cell lung carcinoma. Activation of AP-1 can either stimulate or repress transcription of multiple gene targets, ultimately leading to increased cell proliferation and inhibition of apoptosis. In the present study, we show induction of AP-1 in carcinogen-induced mouse lung tumors compared with surrounding normal lung tissue. We then used a transgenic mouse model directing conditional expression of the dominant-negative c-jun mutant TAM67 in lung epithelial cells to determine the effect of AP-1 inhibition on mouse lung tumorigenesis. Consistent with low AP-1 activity in normal lung tissue, TAM67 expression had no observed effects in adult mouse lung. TAM67 decreased tumor number and overall lung tumor burden in chemically induced mouse lung tumor models. The most significant inhibitory effect was observed on carcinoma burden compared with lower-grade lesions. Our results support the concept that AP-1 is a key regulator of mouse lung tumorigenesis, and identify AP-1-dependent transcription as a potential target to prevent lung tumor progression.
authors: Department of Surgery, The Alvin J. Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA. tichelaarj@wustl.edu
authors: Jay W
authors: JW
authors: Tichelaar
authors: Ying
authors: Y
authors: Yan
authors: Qing
authors: Q
authors: Tan
authors: Yian
authors: Y
authors: Wang
authors: Richard D
authors: RD
authors: Estensen
authors: Matthew R
authors: MR
authors: Young
authors: Nancy H
authors: NH
authors: Colburn
authors: Hulian
authors: H
authors: Yin
authors: Colleen
authors: C
authors: Goodin
authors: Marshall W
authors: MW
authors: Anderson
authors: Ming
authors: M
authors: You
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene; D002273:Carcinogens; D002277:Carcinoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology; D016758:Genes, jun; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology*; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000235:genetics
chemical_list: D002273:Carcinogens; D050505:Mutant Proteins; D010446:Peptide Fragments; D016755:Proto-Oncogene Proteins c-jun; C439528:TAM67 peptide; D018808:Transcription Factor AP-1; D001564:Benzo(a)pyrene