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Identification of DOK genes as lung tumor suppressors.

Nature genetics | Mar 24, 2010

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.

Pubmed ID: 20139980 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Adenocarcinoma | Animals | Cell Proliferation | DNA-Binding Proteins | Gene Expression Regulation, Neoplastic | Genes, Tumor Suppressor | Genetic Predisposition to Disease | Humans | Lung Neoplasms | Mice | Mice, Knockout | Mice, Nude | Phosphoproteins | RNA-Binding Proteins | Transplantation, Heterologous | Tumor Burden | Tumor Cells, Cultured

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Associated grants

  • Agency: NCI NIH HHS, Id: P01 CA129243-049001
  • Agency: NCI NIH HHS, Id: R01 CA132591
  • Agency: NCI NIH HHS, Id: P01 CA064593
  • Agency: NCI NIH HHS, Id: CA-64593
  • Agency: NCI NIH HHS, Id: R01 CA142787
  • Agency: NCI NIH HHS, Id: CA-129243
  • Agency: NCI NIH HHS, Id: P01 CA129243
  • Agency: NCI NIH HHS, Id: P01 CA064593-08A20002

Mouse Genome Informatics (Data, Gene Annotation)

Comparative Toxicogenomics Database (Data, Disease Annotation)

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