Abstract 1229: E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis

2015 ◽  
Author(s):  
Cen Zhang ◽  
Juan Liu ◽  
Xiaolong Wang ◽  
Ken H. Young ◽  
Wenwei Hu ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Tumor Suppressor P53

scholarly journals Competitive ubiquitination activates the tumor suppressor p53

2019 ◽  
Vol 27 (6) ◽  
pp. 1807-1818 ◽  
Author(s):  
Xingyao Li ◽  
Mengqi Guo ◽  
Lun Cai ◽  
Tingting Du ◽  
Ying Liu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Catalytic Activity ◽  
Tumor Suppressor ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Activating Transcription Factor 3 ◽  
Tumor Suppressor P53 ◽  
Unknown Mechanism ◽  
P53 Activation ◽  
Activating Transcription Factor

AbstractBlocking p53 ubiquitination through disrupting its interaction with MDM2 or inhibiting the MDM2 catalytic activity is the central mechanism by which the tumor suppressor p53 is activated in response to genotoxic challenges. Although MDM2 is first characterized as the major E3 ubiquitin ligase for p53, it can also catalyze the conjugation of ubiquitin moieties to other proteins (e.g., activating transcription factor 3, or ATF3). Here we report that ATF3 can act as an ubiquitin “trap” and competes with p53 for MDM2-mediated ubiquitination. While ATF3-mediated p53 stabilization required ATF3 binding to the MDM2 RING domain, we demonstrated that ATF3 ubiquitination catalyzed by MDM2 was indispensable for p53 activation in response to DNA damage. Moreover, a cancer-derived ATF3 mutant (R88G) devoid of ubiquitination failed to prevent p53 from MDM2-mediated degradation and thus was unable to activate the tumor suppressor. Therefore, we have identified a previously-unknown mechanism that can activate p53 in the genotoxic response.

scholarly journals E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis

2014 ◽  
Vol 21 (11) ◽  
pp. 1792-1804 ◽  
Author(s):  
Ju Liu ◽  
C Zhang ◽  
X L Wang ◽  
P Ly ◽  
V Belyi ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Tumor Suppressor P53

scholarly journals An E3 Ubiquitin Ligase RNF139 Serves as a Tumor-Suppressor in Glioma

2021 ◽  
Author(s):  
Xiaofeng Chen ◽  
Weiping Kuang ◽  
Yong Zhu ◽  
Bin Zhou ◽  
Xiaosong Li ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cell Lines ◽  
Ubiquitin Ligase ◽  
Glioma Cell ◽  
Protein Modification ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Glioma Cells ◽  
Migration And Invasion ◽  
Tissue Samples

AbstractGlioma is highly lethal because of its high malignancy. Ubiquitination, a type of ubiquitin-dependent protein modification, has been reported to play an oncogenic or tumor-suppressive role in glioma development, depending on the targets. Ring finger protein 139 (RNF139) is a membrane-bound E3 ubiquitin ligase serving as a tumor suppressor by ubiquitylation-dependently suppressing cell growth. Herein, we firstly confirmed the abnormal downregulation of RNF139 in glioma tissues and cell lines. In glioma cells, ectopic RNF139 overexpression could inhibit, whereas RNF139 knockdown could aggravate the aggressive behaviors of glioma cells, including hyperproliferation, migration, and invasion. Moreover, in two glioma cell lines, RNF139 overexpression inhibited, whereas RNF139 knockdown enhanced the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and AKT serine/threonine kinase 1 (AKT). In a word, we demonstrate the aberration in RNF139 expression in glioma tissue samples and cell lines. RNF139 serves as a tumor-suppressor in glioma by inhibiting glioma cell proliferation, migration, and invasion and promoting glioma cell apoptosis through regulating PI3K/AKT signaling.

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.

The Ubiquitin Ligase COP1 Promotes Glioma Cell Proliferation by Preferentially Downregulating Tumor Suppressor p53

2016 ◽  
Vol 54 (7) ◽  
pp. 5008-5016 ◽  
Author(s):  
Shenshan Zou ◽  
Yufu Zhu ◽  
Bin Wang ◽  
Fengyuan Qian ◽  
Xiang Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Ubiquitin Ligase ◽  
Glioma Cell ◽  
Tumor Suppressor P53 ◽  
Glioma Cell Proliferation

scholarly journals Altered Expression and Localization of Tumor Suppressive E3 Ubiquitin Ligase SMURF2 in Human Prostate and Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 556 ◽  
Author(s):  
Andrea Emanuelli ◽  
Dhanoop Manikoth Ayyathan ◽  
Praveen Koganti ◽  
Pooja Anil Shah ◽  
Liat Apel-Sarid ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Ubiquitin Ligase ◽  
Nuclear Export ◽  
E3 Ubiquitin Ligase ◽  
Subcellular Fractionation ◽  
Normal Cells ◽  
Altered Expression ◽  
Cytoplasmic Accumulation ◽  
Primary Focus ◽  
Cancer Tissues

SMURF2, an E3 ubiquitin ligase and suggested tumor suppressor, operates in normal cells to prevent genomic instability and carcinogenesis. However, the mechanisms underlying SMURF2 inactivation in human malignancies remain elusive, as SMURF2 is rarely found mutated or deleted in cancers. We hypothesized that SMURF2 might have a distinct molecular biodistribution in cancer versus normal cells and tissues. The expression and localization of SMURF2 were analyzed in 666 human normal and cancer tissues, with primary focus on prostate and breast tumors. These investigations were accompanied by SMURF2 gene expression analyses, subcellular fractionation and biochemical studies, including SMURF2’s interactome analysis. We found that while in normal cells and tissues SMURF2 has a predominantly nuclear localization, in prostate and aggressive breast carcinomas SMURF2 shows a significantly increased cytoplasmic sequestration, associated with the disease progression. Mechanistic studies showed that the nuclear export machinery was not involved in cytoplasmic accumulation of SMURF2, while uncovered that its stability is markedly increased in the cytoplasmic compartment. Subsequent interactome analyses pointed to 14-3-3s as SMURF2 interactors, which could potentially affect its localization. These findings link the distorted expression of SMURF2 to human carcinogenesis and suggest the alterations in SMURF2 localization as a potential mechanism obliterating its tumor suppressor activities.

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