A genome-wide screen for loci of common integration in MoMuLV-induced rat T cell lymphomas, led to the identification of a novel oncogene, Jcf1, which is the subject of this proposal. Jcf1is unique among oncogenes, in that it promotes the growth of primary tumor cells in animals but is dispensable in culture. The protein encoded by this gene is 1336 amino acids long, contains a jumonji (JmjC) domain, a CXXC/PHD2 zinc finger domain, an F box and a leucine rich repeat (LRR) and is localized in the nucleus. Underscoring the importance of the JmjC domain, which is thought to be involved in chromatin modification and remodeling, was the finding that three additional provirus integrations among 146 cloned had targeted genes that also encode JmjC domain-containing proteins. A two-hybrid screen using the F-box/LRR domain as the bait identified several interacting proteins that are involved in transcription, DNA repair and the regulation of apoptosis. Moreover, stable or transient transfections of Jcf1in cell lines that express this gene at very low levels induced the expression of the endogenous gene, thus confirming that Jcf1is a regulator gene expression. Serum starvation of NIH 3T3 cells and IL-2 starvation of an IL-2 dependent T cell lymphoma line led to a precipitous drop in Jcf1expression. Reexposure to serum or IL-2 respectively induced Jcf1rapidly, suggesting that Jcf1may have a role in the reentry and progression of cells through the G1 phase of the cell cycle. Moreover, the expression of Jcf1declined to undetectable levels in the course of differentiation of a myelomonocytic cell line in culture suggesting that it may have a role in myeloid cell differentiation. Jcf1is a highly conserved protein. Using preexisting Jcf1Drosphila mutants, generated by P element insertions in the first two introns of the gene, we demonstrated that DJcf1 is required during development. Experiments proposed here will utilize molecular biology, tissue culture and genetic strategies to address the role of Jcf1in development and oncogenesis.
|Sourvinos, George; Morou, Antigoni; Sanidas, Ioannis et al. (2014) The downregulation of GFI1 by the EZH2-NDY1/KDM2B-JARID2 axis and by human cytomegalovirus (HCMV) associated factors allows the activation of the HCMV major IE promoter and the transition to productive infection. PLoS Pathog 10:e1004136|
|Kottakis, Filippos; Foltopoulou, Parthena; Sanidas, Ioannis et al. (2014) NDY1/KDM2B functions as a master regulator of polycomb complexes and controls self-renewal of breast cancer stem cells. Cancer Res 74:3935-46|
|Kottakis, Filippos; Polytarchou, Christos; Foltopoulou, Parthena et al. (2011) FGF-2 regulates cell proliferation, migration, and angiogenesis through an NDY1/KDM2B-miR-101-EZH2 pathway. Mol Cell 43:285-98|
|Kampranis, Sotirios C; Tsichlis, Philip N (2009) Histone demethylases and cancer. Adv Cancer Res 102:103-69|
|Tzatsos, Alexandros; Pfau, Raymond; Kampranis, Sotirios C et al. (2009) Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus. Proc Natl Acad Sci U S A 106:2641-6|
|Pfau, Raymond; Tzatsos, Alexandros; Kampranis, Sotirios C et al. (2008) Members of a family of JmjC domain-containing oncoproteins immortalize embryonic fibroblasts via a JmjC domain-dependent process. Proc Natl Acad Sci U S A 105:1907-12|
|Polytarchou, Christos; Pfau, Raymond; Hatziapostolou, Maria et al. (2008) The JmjC domain histone demethylase Ndy1 regulates redox homeostasis and protects cells from oxidative stress. Mol Cell Biol 28:7451-64|