title: Cigarette Smoke Mediates Nuclear to Cytoplasmic Trafficking of Transcriptional Inhibitor Kaiso through MUC1 and P120-Catenin.
abstract: Lung cancer is the leading cause of cancer-related death, and 87% of these deaths are directly attributable to smoking. Using three-dimensional cultures of primary human bronchial epithelial cells, we demonstrated that loss of adherens junction protein, epithelial cadherin, and the aberrant interaction of its adherens junction binding partner, p120-catenin (p120ctn), with the cytoplasmic tail of apical mucin-1 (MUC1-CT) represent initiating steps in the epithelial-to-mesenchymal transition. Smoke provoked the rapid nuclear entry of p120ctn in complex with MUC1-CT that was inhibited using the MUC1-CT inhibitory peptides, PMIP and GO-201. Nuclear entry of p120ctn promoted its interaction with transcriptional repressor kaiso and the rapid shuttling of kaiso to the cytoplasm. Nuclear exit of kaiso permitted the up-regulation of oncogenic transcription factors Fos/phospho-Ser32Fos, FosB, Fra1/phospho-Ser265Fra1, which was inhibited through suppression of p120ctn's nuclear export using leptomycin-B. These data indicated that smoke-induced nuclear-to-cytoplasmic translocation of kaiso depends on the nuclear import of p120ctn in complex with MUC1-CT and the nuclear export of kaiso in complex with p120ctn. The presence of MUC1-CT/p120ctn and p120ctn/kaiso complexes in lung squamous cell carcinoma and adenocarcinoma specimens from human patients confirms the clinical relevance of these events. Thus, enhancing kaiso's suppressor role of protumor genes by sequestering kaiso in the nucleus of a smoker's airway epithelium may represent a novel approach of treating lung cancer.
authors.affiliation: Francis I. Proctor Foundation, University of California, San Francisco, San Francisco, California.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Francis I. Proctor Foundation, University of California, San Francisco, San Francisco, California.
authors.forename: Marianne
authors.initials: M
authors.lastname: Gallup
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California.
authors.forename: Lorna
authors.initials: L
authors.lastname: Zlock
authors.affiliation: Francis I. Proctor Foundation, University of California, San Francisco, San Francisco, California.
authors.forename: Yu Ting
authors.initials: YT
authors.lastname: Feeling Chen
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California.
authors.forename: Walter E
authors.initials: WE
authors.lastname: Finkbeiner
authors.affiliation: Francis I. Proctor Foundation, University of California, San Francisco, San Francisco, California; Department of Anatomy and Ophthalmology, University of California, San Francisco, San Francisco, California; School of Optometry and Vision Science Graduate Program, University of California, Berkeley, Berkeley, California. Electronic address: nancy.mcnamara@ucsf.edu.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: McNamara
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000368:Aged; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051177:Catenins / Q000378:metabolism*; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018396:Mucin-1 / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D021381:Protein Transport; D012907:Smoking / Q000009:adverse effects*; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation; D000095002:Delta Catenin
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D051177:Catenins; C549568:GO 201; C060192:MUC1 protein, human; D018396:Mucin-1; C570660:PMIP peptide; D010455:Peptides; D014157:Transcription Factors; C492254:ZBTB33 protein, human; D000095002:Delta Catenin; C000722347:CTNND1 protein, human