Members of a family of JmjC domain-containing oncoproteins immortalize embryonic fibroblasts via a JmjC domain-dependent process

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 6; pp. 1907 - 1912
• Main Authors: Pfau, Raymond, Tzatsos, Alexandros, Kampranis, Sotirios C, Serebrennikova, Oksana B, Bear, Susan E, Tsichlis, Philip N
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 12.02.2008; National Acad Sciences
• Subjects: Amino Acid Sequence; Animals; Animals, Newborn; Antibodies; Biochemistry; Biological Sciences; Blotting, Northern; Blotting, Western; Cancer; Cell cycle; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cellular senescence; Embryo, Mammalian - chemistry; Fibroblasts - cytology; Gene expression; HCT116 cells; Histones; Lymphoma, T-Cell - pathology; Lymphoma, T-Cell - virology; Mice; Molecular Sequence Data; Moloney murine leukemia virus - physiology; Oncogene Proteins - physiology; Oncology; Proteins; Proviruses; Rats; Rats, Inbred F344; Retinoblastoma Protein - metabolism; Rodents; Stem cells; T cell receptors; T lymphocytes; Telomeres; Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0711865105

A common integration site, cloned from MoMuLV-induced rat T cell lymphomas, was mapped immediately upstream of Not dead yet-1 (Ndy1)/KDM2B, a gene expressed primarily in testis, spleen, and thymus, that is also known as FBXL10 or JHDM1B. Ndy1 encodes a nuclear, chromatin-associated protein that harbors Jumonji C (JmjC), CXXC, PHD, proline-rich, F-box, and leucine-rich repeat domains. Ndy1 and its homolog Ndy2/KDM2A (FBXL11 or JHDM1A), which is also a target of provirus integration in retrovirus-induced lymphomas, encode proteins that were recently shown to possess Jumonji C-dependent histone H3 K36 dimethyl-demethylase or histone H3 K4 trimethyl-demethylase activities. Here, we show that mouse embryo fibroblasts engineered to express Ndy1 or Ndy2 undergo immortalization in the absence of replicative senescence via a JmjC domain-dependent process that targets the Rb and p53 pathways. Knockdown of endogenous Ndy1 or expression of JmjC domain mutants of Ndy1 promote senescence, suggesting that Ndy1 is a physiological inhibitor of senescence in dividing cells and that inhibition of senescence depends on histone H3 demethylation.