Identification of DOK genes as lung tumor suppressors Journal Article
| Authors: | Berger, A. H.; Niki, M.; Morotti, A.; Taylor, B. S.; Socci, N. D.; Viale, A.; Brennan, C.; Szoke, J.; Motoi, N.; Rothman, P. B.; Teruya-Feldstein, J.; Gerald, W. L.; Ladanyi, M.; Pandolfi, P. P. |
| Article Title: | Identification of DOK genes as lung tumor suppressors |
| Abstract: | Genome-wide analyses of human lung adenocarcinoma have identified regions of consistent copy-number gain or loss, but in many cases the oncogenes and tumor suppressors presumed to reside in these loci remain to be determined. Here we identify the downstream of tyrosine kinase (Dok) family members Dok1, Dok2 and Dok3 as lung tumor suppressors. Single, double or triple compound loss of these genes in mice results in lung cancer, with penetrance and latency dependent on the number of lost Dok alleles. Cancer development is preceded by an aberrant expansion and signaling profile of alveolar type II cells and bronchioalveolar stem cells. In human lung adenocarcinoma, we identify DOK2 as a target of copy-number loss and mRNA downregulation and find that DOK2 suppresses lung cancer cell proliferation in vitro and in vivo. Given the genomic localization of DOK2, we propose it as an 8p21.3 haploinsufficient human lung tumor suppressor. © 2010 Nature America, Inc. All rights reserved. |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; human cell; dna-binding proteins; nonhuman; adenocarcinoma; cell proliferation; mouse; animals; mice; mice, knockout; animal tissue; mus; genetic predisposition to disease; lung neoplasms; gene frequency; in vivo study; in vitro study; tumor cells, cultured; protein tyrosine kinase; carcinogenesis; stem cell; rna-binding proteins; tumor suppressor gene; gene expression regulation, neoplastic; lung adenocarcinoma; mice, nude; messenger rna; tumor burden; heterozygosity; genetic susceptibility; gene identification; transplantation, heterologous; adaptor proteins, signal transducing; phosphoproteins; down regulation; genes, tumor suppressor; knockout mouse; protein dok 1; protein dok 2; protein dok 3 |
| Journal Title: | Nature Genetics |
| Volume: | 42 |
| Issue: | 3 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2010-03-01 |
| Start Page: | 216 |
| End Page: | 223 |
| Language: | English |
| DOI: | 10.1038/ng.527 |
| PUBMED: | 20139980 |
| PROVIDER: | scopus |
| PMCID: | PMC2956443 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 6" - "Export Date: 20 April 2011" - "CODEN: NGENE" - "Source: Scopus" |
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