Abstract
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.
| Original language | English |
|---|---|
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 105 |
| Issue number | 6 |
| Pages (from-to) | 1907-12 |
| Number of pages | 6 |
| ISSN | 0027-8424 |
| DOIs | |
| Publication status | Published - 12 Feb 2008 |
| Externally published | Yes |
Keywords
- Amino Acid Sequence
- Animals
- Animals, Newborn
- Blotting, Northern
- Blotting, Western
- Cell Transformation, Neoplastic
- Cell Transformation, Viral
- Embryo, Mammalian
- Fibroblasts
- Lymphoma, T-Cell
- Mice
- Molecular Sequence Data
- Moloney murine leukemia virus
- Oncogene Proteins
- Rats
- Rats, Inbred F344
- Retinoblastoma Protein
- Tumor Suppressor Protein p53