Functional identification of LRF as an oncogene that bypasses RASV12-induced senescence via upregulation of CYCLIN E

Carcinogenesis
Liesbeth C W VredeveldDaniel S Peeper

Abstract

Mutant RAS (RAS(V12)) is known to transform most immortal cells but to induce premature senescence in primary cells. RAS(V12)-induced senescence in murine cells depends on the induction of the ARF/p53 and the retinoblastoma (Rb) family tumor suppressor pathways. We and others have shown previously that oncogene-induced senescence in vitro can be used as a tool to identify new cancer-related genes. In addition, we have shown that oncogene-induced senescence corresponds to an in vivo tumor suppressive mechanism. Therefore, we extended our search for novel genes that bypass of RAS(V12)-induced senescence, with the help of a previously designed unbiased functional screen with cDNA expression libraries. In this screen, we expected to find new mediators feeding into the p53 or Rb pathways or novel signaling factors. We report here the identification of leukemia/lymphoma related factor (Lrf) encoding a transcription factor with a BTB/POZ domain and Krüppel-like zinc fingers. This gene was previously identified as a potential oncogene that is overexpressed in human cancer. We find that LRF enhances E2F-dependent transcription and that it synergizes with RAS(V12) in activating E2F. Indeed, LRF-mediated bypass of RAS(V12)-induced senesce...Continue Reading

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Citations

Jun 19, 2013·Cell Host & Microbe·Cindrilla ChumduriThomas F Meyer
Feb 12, 2013·Blood·Andrea LunardiPier Paolo Pandolfi
Dec 6, 2017·Molecular Medicine Reports·Guang SunXianwen Liang
Dec 12, 2019·Human Genomics·Caterina ConstantinouArgyro Sgourou
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Jan 11, 2021·Mechanisms of Ageing and Development·Eugenia RoupakiaEvangelos Kolettas
Apr 30, 2020·Cancer Letters·Sanjay GuptaShashank Kumar

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