ABSTRACT
We previously defined the HERV-K Np9 as a viral oncogene. Here we report the discovery of a novel oncogene, Np17, which is homologous to the viral Np9 gene and predominantly present in Hominoidea. Np17 is located on chromosome 8, consists of 7 exons, and encodes a 16.8kDa nuclear protein with149 amino-acid residue. Functionally, knockdown of Np17 induced growth inhibition of leukemia cells, whereas enforced expression of Np17 promoted growth of leukemia cells in vitro and in vivo. In human leukemia, Np17 was detected in 59.65% (34/57) of acute myeloid leukemia (AML) patients examined and associated with refractory/relapsed AML. Mechanistically, Np17 decreased p53 levels and its mechanism might be involved in recruiting nuclear MDM2 to p53 for ubiquitin-mediated degradation. These findings reveal that Np17 is a novel oncogene associated with refractory/relapsed leukemia.
Subject(s)
Leukemia/metabolism , Neoplasm Proteins/metabolism , Oncogene Proteins/metabolism , Animals , Case-Control Studies , Cell Proliferation , Female , Gene Expression Regulation, Leukemic , HL-60 Cells , Humans , K562 Cells , Leukemia/genetics , Leukemia/pathology , Mice, Inbred NOD , Mice, SCID , Neoplasm Proteins/genetics , Oncogene Proteins/genetics , Proteolysis , Proto-Oncogene Proteins c-mdm2/metabolism , Signal Transduction , THP-1 Cells , Tumor Suppressor Protein p53/metabolism , UbiquitinationABSTRACT
As phospho-eIF4E (p-eIF4E), unlike total eIF4E (t-eIF4E) essential for normal cells, is specifically required by cancer cells, it is an attractive, yet unrealized, target for anti-tumor intervention. Here we identify a small molecule, homoharringtonine (HHT), that antagonizes p-eIF4E function and eradicates acute myeloid leukemia (AML) expressing high level of p-eIF4E in vitro and in vivo. HHT selectively reduces p-eIF4E levels of leukemia cells without affecting t-eIF4E. HHT targets the phosphorylated serine 209 residue of p-eIF4E and induces p-eIF4E oligomerization, which enhances its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in proteasome-dependent degradation of p-eIF4E via SUMO2/3-mediated SUMOylation. These results suggest that the phosphorylated serine 209 residue of p-eIF4E might be a potential target for developing small molecule-based new therapies for leukemia.
Subject(s)
Eukaryotic Initiation Factor-4E/metabolism , Harringtonines/pharmacology , Leukemia, Myeloid/drug therapy , Serine/metabolism , Acute Disease , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Blotting, Western , Cell Line, Tumor , Dose-Response Relationship, Drug , Eukaryotic Initiation Factor-4E/chemistry , Harringtonines/chemistry , Homoharringtonine , Humans , Interleukin Receptor Common gamma Subunit/deficiency , Interleukin Receptor Common gamma Subunit/genetics , Leukemia, Myeloid/metabolism , Leukemia, Myeloid/pathology , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Molecular Structure , Phosphorylation/drug effects , Proteasome Endopeptidase Complex/metabolism , Protein Multimerization/drug effects , Proteolysis/drug effects , Small Ubiquitin-Related Modifier Proteins/metabolism , Sumoylation/drug effects , Tumor Cells, Cultured , Ubiquitins/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Aberrant ß-catenin activation contributes to a third or more of human hepatocellular carcinoma (HCC), but ß-catenin activation alone is not sufficient to induce liver cancer in mice. Differentiated hepatocytes proliferate upon acute activation of either ß-catenin or the nuclear xenobiotic receptor CAR. These responses are strictly limited and are tightly linked, since ß-catenin is activated in nearly all of the CAR-dependent tumours generated by the tumour promoter phenobarbital. Here, we show that full activation of ß-catenin in the liver induces senescence and growth arrest, which is overcome by combined CAR activation, resulting in uncontrolled hepatocyte proliferation, hepatomegaly and rapid lethality despite maintenance of normal liver function. Combining CAR activation with limited ß-catenin activation induces tumorigenesis, and the tumours share a conserved gene expression signature with ß-catenin-positive human HCC. These results reveal an unexpected route for hepatocyte proliferation and define a murine model of hepatocarcinogenesis with direct relevance to human HCC.
Subject(s)
Carcinogenesis/pathology , Liver/growth & development , Liver/pathology , Receptors, Cytoplasmic and Nuclear/metabolism , beta Catenin/metabolism , Animals , Carcinogenesis/genetics , Carcinoma, Hepatocellular/pathology , Cellular Senescence , Constitutive Androstane Receptor , Disease Models, Animal , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/pathology , Male , Mice, Inbred C57BL , Mutation/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
The liver is able to regenerate itself in response to partial hepatectomy or liver injury. This is accomplished by a complex network of different cell types and signals both inside and outside the liver. Bile acids (BAs) are recently identified as liver-specific metabolic signals and promote liver regeneration by activating their receptors: Farnesoid X Receptor (FXR) and G-protein-coupled BA receptor 1 (GPBAR1, or TGR5). FXR is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. FXR promotes liver regeneration after 70% partial hepatectomy (PHx) or liver injury. Moreover, activation of FXR is able to alleviate age-related liver regeneration defects. Both liver- and intestine-FXR are activated by BAs after liver resection or injury and promote liver regeneration through distinct mechanism. TGR5 is a membrane-bound BA receptor and it is also activated during liver regeneration. TGR5 regulates BA hydrophobicity and stimulates BA excretion in urine during liver regeneration. BA signaling thus represents a novel metabolic pathway during liver regeneration. This article is part of a Special Issue entitled: Nuclear receptors in animal development.
