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Helicobacter pylori pathogen regulates p14ARF tumor suppressor and autophagy in gastric epithelial cells.
Horvat A, Noto JM, Ramatchandirin B, Zaika E, Palrasu M, Wei J, Schneider BG, El-Rifai W, Peek RM, Zaika AI
(2018) Oncogene 37: 5054-5065
MeSH Terms: Antigens, Bacterial, Autophagy, Bacterial Proteins, Cell Line, Tumor, Down-Regulation, Epithelial Cells, Gastric Mucosa, HCT116 Cells, Helicobacter Infections, Helicobacter pylori, Humans, Signal Transduction, Stomach, Stomach Neoplasms, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, Up-Regulation, Virulence Factors
Show Abstract · Added September 25, 2018
Infection with Helicobacter pylori is one of the strongest risk factors for development of gastric cancer. Although these bacteria infect approximately half of the world's population, only a small fraction of infected individuals develops gastric malignancies. Interactions between host and bacterial virulence factors are complex and interrelated, making it difficult to elucidate specific processes associated with H. pylori-induced tumorigenesis. In this study, we found that H. pylori inhibits p14ARF tumor suppressor by inducing its degradation. This effect was found to be strain-specific. Downregulation of p14ARF induced by H. pylori leads to inhibition of autophagy in a p53-independent manner in infected cells. We identified TRIP12 protein as E3 ubiquitin ligase that is upregulated by H. pylori, inducing ubiquitination and subsequent degradation of p14ARF protein. Using isogenic H. pylori mutants, we found that induction of TRIP12 is mediated by bacterial virulence factor CagA. Increased expression of TRIP12 protein was found in infected gastric epithelial cells in vitro and human gastric mucosa of H. pylori-infected individuals. In conclusion, our data demonstrate a new mechanism of ARF inhibition that may affect host-bacteria interactions and facilitate tumorigenic transformation in the stomach.
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19 MeSH Terms
Bacterial CagA protein induces degradation of p53 protein in a p14ARF-dependent manner.
Wei J, Noto JM, Zaika E, Romero-Gallo J, Piazuelo MB, Schneider B, El-Rifai W, Correa P, Peek RM, Zaika AI
(2015) Gut 64: 1040-8
MeSH Terms: Antigens, Bacterial, Bacterial Proteins, Cell Line, Tumor, Epithelium, Gastric Mucosa, Humans, Immunohistochemistry, Stomach Neoplasms, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53
Show Abstract · Added February 19, 2015
OBJECTIVE - Infection with Helicobacter pylori is the strongest known risk factor for adenocarcinoma of the stomach. Tumorigenic transformation of gastric epithelium induced by H. pylori is a highly complex process driven by an active interplay between bacterial virulence and host factors, many aspects of which remain obscure. In this work, we investigated the degradation of p53 tumour suppressor induced by H. pylori.
DESIGN - Expression of p53 protein in gastric biopsies was assessed by immunohistochemistry. Gastric cells were co-cultured with H. pylori strains isolated from high-gastric risk and low-gastric risk areas and assessed for expression of p53, p14ARF and cytotoxin-associated gene A (CagA) by immunoblotting. siRNA was used to inhibit activities of ARF-BP1 and Human Double Minute 2 (HDM2) proteins.
RESULTS - Our analysis demonstrated that H. pylori strains expressing high levels of CagA virulence factor and associated with a higher gastric cancer risk more strongly suppress p53 compared with low-risk strains in vivo and in vitro. We found that degradation of p53 induced by bacterial CagA protein is mediated by host HDM2 and ARF-BP1 E3 ubiquitin ligases, while the p14ARF protein counteracts H. pylori-induced signalling.
CONCLUSIONS - Our results provide novel evidence that tumorigenicity associated with H. pylori infection is linked to inhibition of p53 protein by CagA. We propose a model in which CagA-induced degradation of p53 protein is determined by a relative level of p14ARF. In cells in which p14ARF levels were decreased due to hypermethylation or deletion of the p14ARF gene, H. pylori efficiently degraded p53, whereas p53 is protected in cells expressing high levels of p14ARF.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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10 MeSH Terms
Characterization and drug resistance patterns of Ewing's sarcoma family tumor cell lines.
May WA, Grigoryan RS, Keshelava N, Cabral DJ, Christensen LL, Jenabi J, Ji L, Triche TJ, Lawlor ER, Reynolds CP
(2013) PLoS One 8: e80060
MeSH Terms: Antineoplastic Agents, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p16, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Humans, Sarcoma, Ewing, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53
Show Abstract · Added February 8, 2016
Despite intensive treatment with chemotherapy, radiotherapy and surgery, over 70% of patients with metastatic Ewing's Sarcoma Family of Tumors (EFT) will die of their disease. We hypothesize that properly characterized laboratory models reflecting the drug resistance of clinical tumors will facilitate the application of new therapeutic agents to EFT. To determine resistance patterns, we studied newly established EFT cell lines derived from different points in therapy: two established at diagnosis (CHLA-9, CHLA-32), two after chemotherapy and progressive disease (CHLA-10, CHLA-25), and two at relapse after myeloablative therapy and autologous bone marrow transplantation (post-ABMT) (CHLA-258, COG-E-352). The new lines were compared to widely studied EFT lines TC-71, TC-32, SK-N-MC, and A-673. These lines were extensively characterized with regard to identity (short tandem repeat (STR) analysis), p53, p16/14 status, and EWS/ETS breakpoint and target gene expression profile. The DIMSCAN cytotoxicity assay was used to assess in vitro drug sensitivity to standard chemotherapy agents. No association was found between drug resistance and the expression of EWS/ETS regulated genes in the EFT cell lines. No consistent association was observed between drug sensitivity and p53 functionality or between drug sensitivity and p16/14 functionality across the cell lines. Exposure to chemotherapy prior to cell line initiation correlated with drug resistance of EFT cell lines in 5/8 tested agents at clinically achievable concentrations (CAC) or the lower tested concentration (LTC): (cyclophosphamide (as 4-HC) and doxorubicin at CAC, etoposide, irinotecan (as SN-38) and melphalan at LTC; P<0.1 for one agent, and P<0.05 for four agents. This panel of well-characterized drug-sensitive and drug-resistant cell lines will facilitate in vitro preclinical testing of new agents for EFT.
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9 MeSH Terms
ARF represses androgen receptor transactivation in prostate cancer.
Lu W, Xie Y, Ma Y, Matusik RJ, Chen Z
(2013) Mol Endocrinol 27: 635-48
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Animals, Cell Line, Tumor, Cell Nucleus, Down-Regulation, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, HEK293 Cells, Homeodomain Proteins, Humans, Male, Mice, Molecular Sequence Data, Prostate, Prostate-Specific Antigen, Prostatic Neoplasms, Protein Binding, Protein Transport, Receptors, Androgen, Repressor Proteins, Transcriptional Activation, Tumor Suppressor Protein p14ARF
Show Abstract · Added March 20, 2014
Androgen receptor (AR) signaling is essential for prostate cancer (PCa) development in humans. The initiation of prostate malignancy and progression to a castration-resistant stage are largely contributed by the modulation of AR activity through its coregulatory proteins. We and others previously reported that p14 alternative reading frame (ARF) expression is positively correlated with the disease progression and severity of PCa. Here, we provide evidence that p14ARF physically interacts with AR and functions as an AR corespressor in both an androgen-dependent and androgen-independent manner. Endogenous ARF (p14ARF in human and p19ARF in mouse) and AR colocalize in both human PCa cells in vitro and PCa tissues of mouse and human in vivo. Overexpression of p14ARF in PCa cells significantly attenuates the activities of androgen response region (ARR2)-probasin and prostate-specific antigen (PSA) promoters. The forced expression of p14ARF in cells resulted in a suppression of PSA and NK transcription factor locus 1 (NKX3.1) expression. Conversely, knockdown of endogenous p14ARF in human PCa cells with short hairpin RNA enhanced AR transactivation activities in a dose-dependent and p53-independent manner. Furthermore, we demonstrated that p14ARF binds to both the N-terminal domain and the ligand-binding domain of AR, and the human double minute 2 (HDM2)-binding motif of p14ARF is required for the interaction of p14ARF and AR proteins. p14ARF perturbs the androgen-induced interaction between the N terminus and C terminus of AR. Most importantly, we observed that the expression of PSA is reversely correlated with p14ARF in human prostate tissues. Taken together, our results reveal a novel function of ARF in modulation of AR transactivation in PCa.
1 Communities
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23 MeSH Terms
Epigenetic regulation of the Ink4a-Arf (Cdkn2a) tumor suppressor locus in the initiation and progression of Notch1-driven T cell acute lymphoblastic leukemia.
Volanakis EJ, Boothby MR, Sherr CJ
(2013) Exp Hematol 41: 377-86
MeSH Terms: Animals, Binding Sites, Bone Marrow Cells, Cell Line, Cell Transformation, Neoplastic, Cells, Cultured, Coculture Techniques, Cyclin-Dependent Kinase Inhibitor p16, Disease Progression, Dogs, Epigenesis, Genetic, Flow Cytometry, Gene Expression, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mutation, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Receptor, Notch1, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, T-Lymphocytes, Thymocytes, Tumor Suppressor Protein p14ARF
Show Abstract · Added December 10, 2013
Activating mutations of NOTCH1 and deletion of the INK4A-ARF (CDKN2A) tumor suppressor locus are two of the most frequent genetic alterations in T cell acute lymphoblastic leukemia (T-ALL). In a murine model of T-ALL induced by the intracellular domain of Notch1 (ICN1), the genetic interaction between ICN1 signaling and Arf inactivation is developmentally stage-specific, with a more pronounced requirement for Arf deletion in thymocytes than in bone marrow precursors targeted for transformation. In the thymus, the target cell for transformation is a CD4 and CD8 double-negative progenitor that undergoes T cell receptor beta-chain rearrangement, a cell type in which polycomb silencing of Ink4a-Arf is normally requisite. Epigenetic remodeling during tumor progression licenses Arf as a tumor suppressor and in turn provides the selective pressure for Ink4a-Arf deletion in clonal T-ALLs that emerge.
Copyright © 2013 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
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25 MeSH Terms
A novel nuclear interactor of ARF and MDM2 (NIAM) that maintains chromosomal stability.
Tompkins VS, Hagen J, Frazier AA, Lushnikova T, Fitzgerald MP, di Tommaso A, Ladeveze V, Domann FE, Eischen CM, Quelle DE
(2007) J Biol Chem 282: 1322-33
MeSH Terms: Adenocarcinoma, Ancrod, Animals, Breast Neoplasms, Cell Division, Cell Line, Tumor, Cell Nucleus, Chromosomes, DNA-Binding Proteins, Fibroblasts, Humans, Intracellular Signaling Peptides and Proteins, Mice, Molecular Sequence Data, Nuclear Proteins, Osteosarcoma, Proto-Oncogene Proteins c-mdm2, RNA, Messenger, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53, Ubiquitin
Show Abstract · Added March 5, 2014
The ARF tumor suppressor signals through p53 and other poorly defined anti-proliferative pathways to block carcinogenesis. In a search for new regulators of ARF signaling, we discovered a novel nuclear protein that we named NIAM (nuclear interactor of ARF and MDM2) for its ability to bind both ARF and the p53 antagonist MDM2. NIAM protein is normally expressed at low to undetectable levels in cells because of, at least in part, MDM2-mediated ubiquitination and proteasomal degradation. When reintroduced into cells, NIAM activated p53, caused a G1 phase cell cycle arrest, and collaborated with ARF in an additive fashion to suppress proliferation. Notably, NIAM retains growth inhibitory activity in cells lacking ARF and/or p53, and knockdown experiments revealed that it is not essential for ARF-mediated growth inhibition. Thus, NIAM and ARF act in separate anti-proliferative pathways that intersect mechanistically and suppress growth more effectively when jointly activated. Intriguingly, silencing of NIAM accelerated chromosomal instability, and microarray analyses showed reduced NIAM mRNA expression in numerous primary human tumors. This study identifies a novel protein with tumor suppressor-like behaviors and functional links to ARF-MDM2-p53 signaling.
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1 Members
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21 MeSH Terms
Decreased Mdm2 expression inhibits tumor development induced by loss of ARF.
Wang P, Greiner TC, Lushnikova T, Eischen CM
(2006) Oncogene 25: 3708-18
MeSH Terms: Animals, Cell Proliferation, Cell Transformation, Neoplastic, Cells, Cultured, Chromosome Aberrations, Cyclin-Dependent Kinase Inhibitor p16, Female, Fibroblasts, Gene Expression Regulation, Neoplastic, Heterozygote, Mice, Mice, Mutant Strains, Mice, Nude, Neoplasms, Experimental, Proto-Oncogene Proteins c-mdm2, Tumor Suppressor Protein p14ARF, ras Proteins
Show Abstract · Added March 5, 2014
The tumor suppressor p14/p19(ARF) regulates Mdm2, which is known for controlling the p53 tumor suppressor. Here we report that loss of one allele of Mdm2 in cells that lack ARF resulted in a decreased rate of proliferation, fewer chromosomal aberrations, and suppression of Ras-induced transformation. Moreover, a haploinsufficiency of Mdm2 inhibited spontaneous tumor development in ARF-null mice. Remarkably, Mdm2(+/-)ARF(-/-) mice survived an average of 6 months longer than Mdm2(+/+)ARF(-/-) mice. The spectrum of tumors that arose in Mdm2(+/-)ARF(-/-) mice did not significantly differ from those that developed in mice lacking only ARF. However, the extended tumor latency allowed for the emergence of multiple primary tumors in a third of the Mdm2(+/-)ARF(-/-) mice, as compared to the single tumor type that arose in ARF-null only mice. Therefore, a decrease in Mdm2 levels restored regulation of critical cellular processes that are altered during transformation and that occur in the absence of ARF. Our findings also indicate that Mdm2 can function independently from ARF and imply that targeting Mdm2 in tumors that lack ARF expression should be an effective therapeutic approach.
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17 MeSH Terms
The inv(16) cooperates with ARF haploinsufficiency to induce acute myeloid leukemia.
Moreno-Miralles I, Pan L, Keates-Baleeiro J, Durst-Goodwin K, Yang C, Kim HG, Thompson MA, Klug CA, Cleveland JL, Hiebert SW
(2005) J Biol Chem 280: 40097-103
MeSH Terms: Alleles, Animals, Bone Marrow Cells, Bone Marrow Transplantation, Cyclin-Dependent Kinase Inhibitor p16, DNA, Flow Cytometry, Genes, Reporter, Green Fluorescent Proteins, Humans, Leukemia, Myeloid, Acute, Liver, Mice, Mice, Transgenic, Mutagenesis, NIH 3T3 Cells, Oncogene Proteins, Fusion, Plasmids, Promoter Regions, Genetic, Protein Binding, Recombinant Fusion Proteins, Spleen, Time Factors, Transfection, Translocation, Genetic, Tumor Suppressor Protein p14ARF
Show Abstract · Added June 26, 2014
The inv(16) is one of the most frequent chromosomal translocations associated with acute myeloid leukemia (AML) and creates a chimeric fusion protein consisting of most of the runt-related X1 co-factor, core binding factor beta fused to the smooth muscle myosin heavy chain MYH11. Expression of the ARF tumor suppressor is regulated by runt-related X1, suggesting that the inv(16) fusion protein (IFP) may repress ARF expression. We established a murine bone marrow transplant model of the inv(16) in which wild type, Arf+/-, and Arf-/- bone marrow were engineered to express the IFP. IFP expression was sufficient to induce a myelomonocytic AML even when expressed in wild type bone marrow, yet removal of only a single allele of Arf greatly accelerated the disease, indicating that Arf is haploinsufficient for the induction of AML in the presence of the inv(16).
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26 MeSH Terms
A novel ARF-binding protein (LZAP) alters ARF regulation of HDM2.
Wang J, He X, Luo Y, Yarbrough WG
(2006) Biochem J 393: 489-501
MeSH Terms: Alternative Splicing, Amino Acid Sequence, Animals, Base Sequence, Carrier Proteins, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Mice, Molecular Sequence Data, Nerve Tissue Proteins, Protein Binding, Proto-Oncogene Proteins c-mdm2, Rabbits, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53, Ubiquitin
Show Abstract · Added March 5, 2014
The tumour suppressor ARF (alternative reading frame) is encoded by the INK4a (inhibitor of cyclin-dependent kinase 4)/ARF locus, which is frequently altered in human tumours. ARF binds MDM2 (murine double minute 2) and releases p53 from inhibition by MDM2, resulting in stabilization, accumulation and activation of p53. Recently, ARF has been found to associate with other proteins, but, to date, little is known about ARF-associated proteins that are implicated in post-translational regulation of ARF activity. Using a yeast two-hybrid screen, we have identified a novel protein, LZAP (LXXLL/leucine-zipper-containing ARF-binding protein), that interacts with endogenous ARF in mammalian cells. In the present study, we show that LZAP reversed the ability of ARF to inhibit HDM2's ubiquitin ligase activity towards p53, but simultaneously co-operated with ARF, maintaining p53 stability and increasing p53 transcriptional activity. Expression of LZAP, in addition to ARF, increased the percentage of cells in the G1 phase of the cell cycle. Expression of LZAP also caused activation of p53 and a p53-dependent G1 cell-cycle arrest in the absence of ARF. Taken together, our data suggest that LZAP can regulate ARF biochemical and biological activity. Additionally, LZAP has p53-dependent cell-cycle effects that are independent of ARF.
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20 MeSH Terms
Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants.
Hemann MT, Bric A, Teruya-Feldstein J, Herbst A, Nilsson JA, Cordon-Cardo C, Cleveland JL, Tansey WP, Lowe SW
(2005) Nature 436: 807-11
MeSH Terms: Adoptive Transfer, Alleles, Animals, Apoptosis, Apoptosis Regulatory Proteins, Bcl-2-Like Protein 11, Burkitt Lymphoma, Carrier Proteins, Cell Cycle Proteins, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p21, Genes, myc, Humans, Membrane Proteins, Mice, Mice, Inbred C57BL, Mutation, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-myc, Stem Cell Transplantation, Tumor Suppressor Protein p14ARF, Tumor Suppressor Protein p53
Show Abstract · Added March 10, 2014
The c-Myc oncoprotein promotes proliferation and apoptosis, such that mutations that disable apoptotic programmes often cooperate with MYC during tumorigenesis. Here we report that two common mutant MYC alleles derived from human Burkitt's lymphoma uncouple proliferation from apoptosis and, as a result, are more effective than wild-type MYC at promoting B cell lymphomagenesis in mice. Mutant MYC proteins retain their ability to stimulate proliferation and activate p53, but are defective at promoting apoptosis due to a failure to induce the BH3-only protein Bim (a member of the B cell lymphoma 2 (Bcl2) family) and effectively inhibit Bcl2. Disruption of apoptosis through enforced expression of Bcl2, or loss of either Bim or p53 function, enables wild-type MYC to produce lymphomas as efficiently as mutant MYC. These data show how parallel apoptotic pathways act together to suppress MYC-induced transformation, and how mutant MYC proteins, by selectively disabling a p53-independent pathway, enable tumour cells to evade p53 action during lymphomagenesis.
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24 MeSH Terms