Members of a family of JmjC domain-containing oncoproteins immortalize embryonic fibroblasts via a JmjC domain-dependent process.
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.
Pfau
Raymond
R
Molecular Oncology Research Institute, Tufts-New England Medical Center, 75 Kneeland Street, Boston, MA 02111, USA.
Tzatsos
Alexandros
A
Kampranis
Sotirios C
SC
Serebrennikova
Oksana B
OB
Bear
Susan E
SE
Tsichlis
Philip N
PN
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D004622:Embryo, Mammalian / Q000737:chemistry*; D005347:Fibroblasts / Q000166:cytology; D016399:Lymphoma, T-Cell / Q000473:pathology / Q000821:virology; D051379:Mice; D008969:Molecular Sequence Data; D008979:Moloney murine leukemia virus / Q000502:physiology; D015513:Oncogene Proteins / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D015513:Oncogene Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53