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Oncogene. 2014 Jul 3;33(27):3594-603. doi: 10.1038/onc.2013.316. Epub 2013 Aug 12.

Pleiotropic effect of somatic mutations in the E2F subunit DP-1 gene in human cancer.

Author information

1
Department of Oncology, Laboratory of Cancer Biology, Medical Sciences Division, University of Oxford, Oxford, UK.
2
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences University of Oxford, Nuffield Orthopaedic Centre, Windmill Road, Oxford, UK.

Abstract

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.

PMID:
23934193
DOI:
10.1038/onc.2013.316
[Indexed for MEDLINE]

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