Pleiotropic effect of somatic mutations in the E2F subunit DP-1 gene in human cancer.
Transcription factor E2F-1 and its interaction with pRb provide a key point of control in cell proliferation. E2F-1 participates in both cell cycle progression and apoptosis, and in cells exists with a DP dimerization partner protein, the most prominent being DP-1. By mining the tumor tissue and cancer cell line encyclopedia genomic databases, we identified the first somatic mutations in the DP-1 gene and describe 53 distinct mutation events here. The mutations are mostly missense mutations, but also include nonsense and frame-shift mutations that result in truncated DP-1 derivatives. Mutation occurs throughout the DP-1 gene but generally leaves protein dimerization activity intact. This allows the mutant derivatives to affect the properties of the E2F-1/DP-1 heterodimer through a transdominant mechanism, which changes the DNA binding, transcriptional activation and pRb-binding properties of the heterodimer. In particular, many DP-1 mutants were found to impair E2F-1-dependent apoptosis. Our results establish that somatic mutations in DP-1 uncouple normal control of the E2F pathway, and thus define a new mechanism that could contribute to aberrant proliferation in tumor cells.
Department of Oncology, Laboratory of Cancer Biology, Medical Sciences Division, University of Oxford, Oxford, UK.
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Munro
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences University of Oxford, Nuffield Orthopaedic Centre, Windmill Road, Oxford, UK.
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Oppermann
Department of Oncology, Laboratory of Cancer Biology, Medical Sciences Division, University of Oxford, Oxford, UK.
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La Thangue
D000595:Amino Acid Sequence; D017209:Apoptosis; D045744:Cell Line, Tumor; D050687:E2F1 Transcription Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D058685:Genetic Pleiotropy; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D050680:Transcription Factor DP1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D010750:Phosphoproteins; D021122:Protein Subunits; D016160:Retinoblastoma Protein; C493735:TFDP1 protein, human; D050680:Transcription Factor DP1