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

Journal article

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. © 2014 Macmillan Publishers Limited.

Authors: Munro, S; Oppermann, U; La Thangue, N

• Publisher: Nature Publishing Group
• Journal: Oncogene
• Volume: 33
• Issue: 27
• Pages: 3594-3603
• Publication date: 2014-07-03
• DOI: 10.1038/onc.2013.316
• EISSN: 1476-5594
• ISSN: 0950-9232
• Language: English
• Keywords: DP-1; somatic mutation; cancer; E2F