scholarly journals Overexpression of E3 ubiquitin ligase tripartite motif 32 correlates with a poor prognosis in patients with gastric cancer

2017 ◽  
Vol 13 (5) ◽  
pp. 3131-3138 ◽  
Author(s):  
Masahiro Ito ◽  
Kazuhiro Migita ◽  
Sohei Matsumoto ◽  
Kohei Wakatsuki ◽  
Tetsuya Tanaka ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Ubiquitin Ligase ◽  
Poor Prognosis ◽  
E3 Ubiquitin Ligase ◽  
Tripartite Motif

TRIM65 in White Matter Lesions, Innate Immunity and Tumor

2021 ◽  
Vol 14 ◽  
Author(s):  
Bingxue Liu ◽  
Yunlian Tang ◽  
Ping Yang ◽  
Chu Wu ◽  
Yue Huang
Keyword(s):  
Signal Transduction ◽  
Innate Immunity ◽  
White Matter ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
White Matter Lesions ◽  
Intracellular Signal Transduction ◽  
Cellular Processes ◽  
Tripartite Motif ◽  
Intracellular Signal

Abstract: Most of the tripartite motif (TRIM) family proteins have E3 ubiquitin ligase activities and also have a variety of functions in cellular processes such as intracellular signal transduction, apoptosis, innate immunity and carcinogenesis. TRIM65 is a member of the TRIM family. More and more evidences have shown a unique and importance of TRIM65 protein in the occurrence and development of some diseases. In this review, the importance on TRIM65 in white matter lesions, innate immunity and the effect of tumors was mainly reviewed.

Regulation of p14ARF by Siva1 in H. pylori-infected gastric epithelial cells.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 243-243
Author(s):  
Manikandan Palrasu ◽  
Elena Zaika ◽  
El-Rifai Wael ◽  
Richard Peek ◽  
Alexander Zaika
Keyword(s):  
Gastric Cancer ◽  
Tumor Suppressor ◽  
Epithelial Cells ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Bacterial Degradation ◽  
Tumor Suppressor Protein ◽  
Gastric Epithelial Cells ◽  
H Pylori ◽  
Oncogenic Stress

243 Background: Helicobacter pylori ( H. pylori) is the strongest known risk factor for gastric cancer. Bacterial degradation of tumor suppressor proteins affect the host microbe’s interactions and host cellular response, which contribute to tumorigenesis. p14ARF, a crucial tumor suppressor protein that activates p53 protein under oncogenic stress plays a major role in oncogenic stress response (OSR) regulation. However, little is known about the mechanism of ARF and OSR regulation in H. pylori-infected gastric epithelial cells. Methods: The expression of p14ARF and cytotoxin-associated gene A (CagA) were analyzed in gastric cells co-cultured with H. pylori strains isolated from high-gastric risk and low-gastric risk areas by immunoblotting. To investigate the potential role of CagA in regulation of p14ARF, we employed isogenic cagA− and cagE− H. pylori mutants in gastric epithelial cells, and C57BL/6 mice (n = 10). We also analyzed the expression of Siva1 in human individual infected with cagA-positive (n = 13) and cagA-negative (n = 13) bacteria as well as uninfected human subjects (n = 6). siRNA was used to inhibit activity of Siva1 protein. Results: In this study, H. pylori strains expressing high levels of CagA virulence factor and associated with a higher gastric cancer risk more strongly suppress p14ARF compared with low-risk strains in vivo and in vitro. We found that degradation of p14ARF induced by CagA is mediated by E3 ubiquitin ligase Siva1, which works in concert with another E3 ubiquitin ligase TRIP12. Decreased expression of Siva1 protein and consequent up-regulation of p14ARF was also found in gastric mucosa of H. pylori-infected mice and human individuals. Tumorigenic strain 7.13 was more potent in upregulation of Siva1 and downregulation of p14ARF than non-tumorigenic strain B128. Inhibition of p14ARF protein by H. pylori causes inhibition of autophagy in infected cells. Conclusions: Our results provide first evidence that carcinogenic H. pylori strains significantly alter the host tumor suppressor protein p14ARF, leading to suppression of host OSR and autophagy, which may affect host-bacteria interactions and tumorigenic alteration in the stomach.

E3 ubiquitin ligase tripartite motif 7 positively regulates the TLR4-mediated immune response via its E3 ligase domain in macrophages

2019 ◽  
Vol 109 ◽  
pp. 126-133 ◽  
Author(s):  
Mingfeng Lu ◽  
Xuhui Zhu ◽  
Zhizhou Yang ◽  
Wei Zhang ◽  
Zhaorui Sun ◽  
...  
Keyword(s):  
Immune Response ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
E3 Ligase ◽  
Tripartite Motif

Frequent Detection of C-Cbl Homozygous Mutation in Secondary Myelogeneous Leukemia Transformed from MDS/MPD with Chromosome 11q Uniparental Disomy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 851-851 ◽  
Author(s):  
Hideki Makishima ◽  
Andrew J Dunbar ◽  
Anna M Jankowska ◽  
Lukasz P. Gondek ◽  
Eric D Hsi ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Copy Number ◽  
Poor Prognosis ◽  
Uniparental Disomy ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Blast Transformation ◽  
Missense Mutations ◽  
Ring Finger Domain ◽  
History Of

Abstract Two types of acquired loss of heterozygosity are possible in cancer: deletions and copy-neutral uniparental disomy (UPD). Conventionally, copy number losses are identified using metaphase cytogenetics while detection of UPD is accomplished by microsatellite and copy number analysis and as such, is not often used clinically. Recently, introduction of single nucleotide polymorphism microarrays (SNP-A) have allowed for the systematic and sensitive detection of UPD in hematological malignancies and other cancers. In this study, we have applied Affymetrics 250K and 6.0 SNP-A technology to detect previously cryptic chromosomal changes, particularly UPD, in a cohort of 301 patients with myelodysplastic syndromes (MDS), overlap MDS/myeloproliferative disorders (MPD), MPD, and primary and secondary acute myeloid leukemia (AML). When appropriate, germ line DNA was analyzed to confirm somatic nature of the suspected lesions. We show that UPD is a common chromosomal defect in myeloid malignancies, particularly in chronic myelomonocytic leukemia (CMML; 52%) and MDS/MPD-unclassifiable (49%). Furthermore, we demonstrate that mapping minimally overlapping segmental UPD regions can help target the search for both known and unknown pathogenic mutations. Chromosomes frequently affected by UPD include 1p (N=12), 4q (N=11), 6p (N=9), 7q (N=9), 9p (N=11), 13 (N=11), 17 (N=11), and 21 (N=7). The chromosome arm most often affected was 11q, occurring in 15/301 patients, 8 of which had MDS/MPDu, CMML or AML evolving from these conditions. These patients with UPD11q appear to display several common clinical phenotypic trends, including history of MDS/MPD, the presence of monocytic blasts or increased numbers of differentiated monocytes, propensity to transformation, and poor prognosis. Given the prevalence of UPD on chromosome 11q, we screened for candidate genes located in this region. Among our UPD11q cohort, the lesions of 12/15 patients were located in the region of the c-Cbl gene encoding the E3 ubiquitin ligase involved in the degradation of active protein tyrosine kinase receptors. Direct genomic sequencing of c-Cbl in these patients revealed the presence of 3 unique missense mutations, all occurring within or directly adjacent to the RING finger domain responsible for ubiquitination activity. In total, 7/12 patients with UPD11q showed c-Cbl mutation. One mutation, occurring in 2/7 patients, resulted in the substitution of an arginine with either glutamine or proline at position 420 (R420Q/P) located just outside the RING domain. However, we also found 2 additional, newly-identified missense mutations, both affecting the cysteines of the RING finger in the remaining 5 patients. In 2/5 patients, residue 384 was altered by substitution of a tyrosine. In the other 3 patients, residue 404 was altered by substitution of either a tyrosine (in 1 patient) or serine (in 2 patients). When additional 71 patients with similar phenotypic features but negative for UPD11q were screened, 2 novel c-Cbl mutations in RING finger domain (heterozygous) and Linker sequence (monoallelic in deletion 11q) were identified to a total of 9 cases affected by c-Cbl mutations. Analysis of clinical/immunological/pathological phenotype of these patients revealed the history of blast transformation in 77%, presence of monocytosis (over 1000/ul) or monocytic blasts in 88%, poor prognosis in 100% (5 years over all survival; 0%), some degree of marrow fibrosis in 100% and c-kit positivity in 77% of cases. We conclude that invariant mutations in c-Cbl E3 ubiquitin ligase may explain the pathogenesis of a clonal process or subsequent AML transformation in a unique subset of MDS/MPD, including CMML.

Absence Of The E3 Ubiquitin Ligase SKP2 Attenuates Notch-Induced T-Cell Leukemogenesis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1272-1272
Author(s):  
Sonia Rodriguez-Rodriguez ◽  
Lin Wang ◽  
Huajia Zhang ◽  
Amy Zollman ◽  
Angelo Cardoso ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Ubiquitin Ligase ◽  
Poor Prognosis ◽  
Lymphoblastic Leukemia ◽  
E3 Ubiquitin Ligase ◽  
Cell Leukemia ◽  
Skp2 Expression ◽  
T Cell Leukemogenesis

Abstract Acute Lymphoblastic Leukemia (ALL) is the most common malignancy in childhood, accounting for almost 30% of pediatric cancers. In pediatric T-cell acute lymphoblastic leukemia (T-ALL), around 30% of the children still undergo disease relapse, which is associated with poor prognosis. Hence, novel therapeutic strategies for the treatment of T-ALL are necessary, since conventional therapies still fail to cure a significant number of patients. Notch signaling contributes to the regulation of normal T-cells homeostasis, whereas oncogenic, activated form of Notch is present in the majority of the T-ALL cases. Previous studies in our laboratory demonstrated that Notch1 signaling induces transcriptional activation of SKP2, the F-box protein of the SCF E3-ubiquitin ligase complex. SKP2 targets the major cell cycle inhibitors, the CKIs p21Cip1, p27Kip1, p57Kip2 and p130, for proteasome-mediated degradation. Increased Skp2 expression accelerates cell cycle progression in hematopoietic cells, and its overexpression is frequently found in cancers, in particular lymphomas and leukemias, in which is associated with poor prognosis. We found that Skp2 expression is dynamically regulated during T-cell differentiation coinciding with the Notch expression pattern. Moreover, primary thymocytes cultured in vitro responded to Notch stimulation by the Delta1 ligand increasing their Skp2 expression and their cell cycle activity. As anticipated, we found that Skp2 expression is increased in T-ALL patient samples. Our hypothesis is that Notch activation promotes T-cell leukemogenesis by altering the cell cycle control through upregulation of SKP2. To better define the role of SKP2 in T-ALL, we analyzed the Skp2 expression in a murine model of Notch-induced T-cell leukemia. Mice transplanted with stem/progenitor cells transduced with the constitutive active form of Notch (ICN), developed T-ALL and died by week 12 after transplant. Analysis of T-ALL cells revealed a 5 fold upregulation of Skp2 expression compared to controls. Next, we tested whether SKP2 was required for T-ALL development. To this end, we evaluated leukemia development in mice transplanted with SKP2 deficient cells overexpressing ICN. Stem/progenitor cells derived from Skp2+/+, Skp2+/- or Skp2-/- mice were transduced with ICN and then transplanted into WT recipients. Loss of SKP2 significantly delayed the development of T-cell leukemia in transplanted mice and increased their survival by 60% at 12 weeks. Taken together, these results demonstrate a previously unrecognized role for SKP2 in the initiation and progression of T-ALL and its potential role as a therapeutic target. Disclosures: No relevant conflicts of interest to declare.

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