Functional identification of LRF as an oncogene that bypasses RAS super(V12)-induced senescence via upregulation of CYCLIN E

• Published in: Carcinogenesis (New York) 2010-02, Vol.31 (2), p.201-207
• Main Authors: Vredeveld, Liesbeth CW, Rowland, Benjamin D, Douma, Sirith, Bernards, Rene, Peeper, Daniel S
• Format: Article
• Language: English
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgp296

Mutant RAS (RAS super(V12)) is known to transform most immortal cells but to induce premature senescence in primary cells. RAS super(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 super(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 Krueppel-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 super(V12) in activating E2F. Indeed, LRF-mediated bypass of RAS super(V12)-induced senescence is accompanied by the induction of several E2F-target genes, including Cyclin E, Cyclin A and p107. Unexpectedly, LRF exerted this activity independent of several critical senescence inducers, such as p19 super(ARF), p21 super(CIP) and p16 super(INK4A). We show that CYCLIN E is necessary for LRF-mediated bypass, suggesting that it corresponds to a critical mediator of LRF-driven oncogenic transformation. Thus, LRF bypasses RAS super(V12)-induced senescence in a CYCLIN E-dependent manner, which conceivably contributes to its role in cancer.