Journal Article

Functional identification of LRF as an oncogene that bypasses RAS<sup>V12</sup>-induced senescence via upregulation of CYCLIN E

Liesbeth C.W. Vredeveld, Benjamin D. Rowland, Sirith Douma, René Bernards and Daniel S. Peeper

in Carcinogenesis

Volume 31, issue 2, pages 201-207
Published in print February 2010 | ISSN: 0143-3334
Published online November 2009 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgp296
Functional identification of LRF as an oncogene that bypasses RASV12-induced senescence via upregulation of CYCLIN E

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Mutant RAS (RASV12) is known to transform most immortal cells but to induce premature senescence in primary cells. RASV12-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 RASV12-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 RASV12 in activating E2F. Indeed, LRF-mediated bypass of RASV12-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 p19ARF, p21CIP and p16INK4A. 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 RASV12-induced senescence in a CYCLIN E-dependent manner, which conceivably contributes to its role in cancer.

Journal Article.  4668 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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