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E2F7 Is a Potent Inhibitor of Liver Tumor Growth in Adult Mice
Author(s) -
Moreno Eva,
Toussaint Mathilda J.M.,
Essen Saskia C.,
Bongiovanni Laura,
Liere Elsbeth A.,
Koster Mirjam H.,
Yuan Ruixue,
Deursen Jan M.,
Westendorp Bart,
Bruin Alain
Publication year - 2021
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31259
Subject(s) - biology , carcinogenesis , e2f , retinoblastoma protein , retinoblastoma , cell growth , cancer research , transgene , cell cycle , dna replication , cancer , microbiology and biotechnology , genetics , dna , gene
Background and Aims Up‐regulation of the E2F‐dependent transcriptional network has been identified in nearly every human malignancy and is an important driver of tumorigenesis. Two members of the E2F family, E2F7 and E2F8, are potent repressors of E2F‐dependent transcription. They are atypical in that they do not bind to dimerization partner proteins and are not controlled by retinoblastoma protein. The physiological relevance of E2F7 and E2F8 remains incompletely understood, largely because tools to manipulate their activity in vivo have been lacking. Approach and Results Here, we generated transgenic mice with doxycycline‐controlled transcriptional activation of E2f7 and E2f8 and induced their expression during postnatal development, in adulthood, and in the context of cancer. Systemic induction of E2f7 and, to lesser extent, E2f8 transgenes in juvenile mice impaired cell proliferation, caused replication stress, DNA damage, and apoptosis, and inhibited animal growth. In adult mice, however, E2F7 and E2F8 induction was well tolerated, yet profoundly interfered with DNA replication, DNA integrity, and cell proliferation in diethylnitrosamine‐induced liver tumors. Conclusion Collectively, our findings demonstrate that atypical E2Fs can override cell‐cycle entry and progression governed by other E2F family members and suggest that this property can be exploited to inhibit proliferation of neoplastic hepatocytes when growth and development have subsided during adulthood.