scholarly journals Targeting Itch/p73 pathway by thymoquinone as a novel therapeutic strategy for cancers with p53 mutation

2020 ◽  
Vol 2 (1) ◽  
pp. 20-26
Author(s):  
Rashad M Alghamdi ◽  
Mohammed A. Hassan ◽  
Mohammed Kaleem ◽  
Asaad Kayali ◽  
Majed A Halwani ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Ubiquitin Ligase ◽  
Therapeutic Strategy ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
E3 Ubiquitin Ligase ◽  
P53 Mutation ◽  
Jurkat Cells ◽  
Biologically Active ◽  
P53 Family

The tumor suppressor p73 is a member of p53 family and has a high degree of similarity with p53 function and structure. Like p53, p73 can also induce the expression of several genes involved in cell cycle and apoptosis. p73 expression is downregulated in many tumors by several mechanisms including the ubiquitination pathway. Thus, understanding the ubiquitin-proteasome pathway in p73 regulation will help in targeting this later and develop a new promising therapeutic strategy for cancer with p53 mutations. The aim of this study was to evaluate the effect of Thymoquinone (TQ), the major biologically active compound of the black seed oil on the expression of several E3 ubiquitin ligase enzymes known to be regulators of p73 and the related events in cancer cells with p53 mutation, such as the human acute lymphoblastic leukemia Jurkat cells, the human triple-negative breast cancer (MDA-MB-468 cells) and human promyelocytic leukemia HL60 cells. RNA-seq data showed that several E3 ubiquitin-ligase enzymes, well documented to be involved in the degradation of p73 including Itch, Pirh2, E3s Pin2, Mdm2, TRIM32 and SCFFBXO45 were downregulated in Jurkat cells. Among the target genes, Itch was significantly downregulated in TQ-treated Jurkat cells as compared with control cells. TQ-induced Itch downregulation was confirmed by real-time RT-PCR in Jurkat cells, MDA-MB-468 cells and HL60. Treating Jurkat cells with either TQ or the proteasome inhibitor MG132 induced an upregulation of p73. The present study indicates that TQ could be a promising inhibitor of the E3-ubiquitin ligase Itch leading to the upregulation of tumor suppressor p73 in cancers expressing mutant 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.

scholarly journals Transcriptional Regulation of Genes by Ikaros Tumor Suppressor in Acute Lymphoblastic Leukemia

2020 ◽  
Vol 21 (4) ◽  
pp. 1377
Author(s):  
Pavan Kumar Dhanyamraju ◽  
Soumya Iyer ◽  
Gayle Smink ◽  
Yevgeniya Bamme ◽  
Preeti Bhadauria ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tumor Suppressor ◽  
Chromatin Remodeling ◽  
Target Genes ◽  
Cellular Proliferation ◽  
Lymphoblastic Leukemia ◽  
Regulatory Elements ◽  
Binding Motif ◽  
Functional Inactivation

Regulation of oncogenic gene expression by transcription factors that function as tumor suppressors is one of the major mechanisms that regulate leukemogenesis. Understanding this complex process is essential for explaining the pathogenesis of leukemia as well as developing targeted therapies. Here, we provide an overview of the role of Ikaros tumor suppressor and its role in regulation of gene transcription in acute leukemia. Ikaros (IKZF1) is a DNA-binding protein that functions as a master regulator of hematopoiesis and the immune system, as well as a tumor suppressor in acute lymphoblastic leukemia (ALL). Genetic alteration or functional inactivation of Ikaros results in the development of high-risk leukemia. Ikaros binds to the specific consensus binding motif at upstream regulatory elements of its target genes, recruits chromatin-remodeling complexes and activates or represses transcription via chromatin remodeling. Over the last twenty years, a large number of Ikaros target genes have been identified, and the role of Ikaros in the regulation of their expression provided insight into the mechanisms of Ikaros tumor suppressor function in leukemia. Here we summarize the role of Ikaros in the regulation of the expression of the genes whose function is critical for cellular proliferation, development, and progression of acute lymphoblastic leukemia.

scholarly journals MiR-486-5p Suppresses Proliferation and Migration of Hepatocellular Carcinoma Cells through Downregulation of the E3 Ubiquitin Ligase CBL

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Jia He ◽  
Bin Xiao ◽  
Xiaoyan Li ◽  
Yongyin He ◽  
Linhai Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Ubiquitin Ligase ◽  
Target Genes ◽  
E3 Ubiquitin Ligase ◽  
Tumor Stage ◽  
Suppressor Gene ◽  
Cell Counting ◽  
And Migration ◽  
Proliferation And Migration

MicroRNAs have been broadly implicated in cancer, but precise functions and mechanisms in carcinogenesis vary among cancer types and in many cases remain poorly understood. Hepatocellular carcinoma (HCC) is among the most frequent and lethal cancers. The aim of the present study was to investigate the role of miR-486-5p in HCC and identify its specific target. MiR-486-5p was significantly downregulated in HCC tissues and cell lines compared with noncancerous tissues and, respectively, although expression level was not correlated with the degree of infiltration or tumor stage. However, miR-486-5p overexpression in HCC cells inhibited proliferation and migration as evidenced by CCK-8 cell counting, wound healing, and transwell assays, indicating that miR-486-5p is an HCC suppressor. We employed four miRNA databases to predict the target genes of miR-486-5p and verified retrieved genes using qPCR and western blotting. The E3 ubiquitin ligase CBL was significantly downregulated by miR-486-5p overexpression in HCC cell lines at both mRNA and protein level, and overexpression of CBL counteracted the inhibitory effects of miR-486-5p on HCC cell proliferation and migration. Moreover, CBL expression was negatively correlated with miR-486-5p expression in HCC tissues. Collectively, our results suggest that miR-486-5p may act as a tumor suppressor gene in HCC by downregulating CBL expression.

scholarly journals KDM2B in polycomb repressive complex 1.1 functions as a tumor suppressor in the initiation of T-cell leukemogenesis

2019 ◽  
Vol 3 (17) ◽  
pp. 2537-2549 ◽  
Author(s):  
Yusuke Isshiki ◽  
Yaeko Nakajima-Takagi ◽  
Motohiko Oshima ◽  
Kazumasa Aoyama ◽  
Mohamed Rizk ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Zinc Finger ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Dependent Manner ◽  
Polycomb Repressive Complex ◽  
Human T Cell ◽  
T Cell Leukemogenesis ◽  
Deficient Mice

Abstract KDM2B together with RING1B, PCGF1, and BCOR or BCORL1 comprise polycomb repressive complex 1.1 (PRC1.1), a noncanonical PRC1 that catalyzes H2AK119ub1. It binds to nonmethylated CpG islands through its zinc finger-CxxC DNA binding domain and recruits the complex to target gene loci. Recent studies identified the loss of function mutations in the PRC1.1 gene, BCOR and BCORL1 in human T-cell acute lymphoblastic leukemia (T-ALL). We previously reported that Bcor insufficiency induces T-ALL in mice, supporting a tumor suppressor role for BCOR. However, the function of BCOR responsible for tumor suppression, either its corepressor function for BCL6 or that as a component of PRC1.1, remains unclear. We herein examined mice specifically lacking the zinc finger-CxxC domain of KDM2B in hematopoietic cells. Similar to Bcor-deficient mice, Kdm2b-deficient mice developed lethal T-ALL mostly in a NOTCH1-dependent manner. A chromatin immunoprecipitation sequence analysis of thymocytes revealed the binding of KDM2B at promoter regions, at which BCOR and EZH2 colocalized. KDM2B target genes markedly overlapped with those of NOTCH1 in human T-ALL cells, suggesting that noncanonical PRC1.1 antagonizes NOTCH1-mediated gene activation. KDM2B target genes were expressed at higher levels than the others and were marked with high levels of H2AK119ub1 and H3K4me3, but low levels of H3K27me3, suggesting that KDM2B target genes are transcriptionally active or primed for activation. These results indicate that PRC1.1 plays a key role in restricting excessive transcriptional activation by active NOTCH1, thereby acting as a tumor suppressor in the initiation of T-cell leukemogenesis.

Rearrangement and Deletion of the PAX5 Gene in Pediatric Acute B-Cell Lineage Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 981-981
Author(s):  
Norihiko Kawamata ◽  
Seishi Ogawa ◽  
Martin Zimmermann ◽  
Masashi Sanada ◽  
Kari Hemminki ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
B Cell ◽  
Point Mutation ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Cell Lineage ◽  
Dominant Negative ◽  
Pax5 Gene

Abstract Pediatric acute lymphoblastic leukemia (ALL) is the most common malignant disease in children. The disease results from accumulation of mutations of tumor suppressor genes and oncogenes. Recently, higher resolution SNP-chips (50,000–500,000 probes) have been developed allowing us to identify genes involved at the start sites of deletions/duplications. This permitted us both to identify unbalanced translocations involving t(1;19)(q23;p13) (TCF3/PBX1) and t(12;21)(p13;q11) (ETV6/RUNX1), as well as, to find novel fusion genes involving PAX5 in B-cell lineage ALL. PAX5 gene was rearranged to a variety of partner genes including ETV6, FOXP1, AUTS2 and C20orf112. In each case, tthe C-terminal end of the PAX5 gene was replaced by the partner gene. The PAX5 fusion gene products suppressed transcriptional activity of PAX5 in a dominant negative fashion. We also found a point mutation of PAX5 at codon 26 (Val 26 Gly); and this mutated PAX5 had attenuated transcriptional activity. Expression of PAX5/C20orf112 fusion gene in a B-cell line suppressed endgenous expression of PAX5 target genes including BLK1 and CD19. Furthermore, deletion of PAX5 was common in B-cell lineage ALL (34/339 cases). PAX5 gene is localized on chromosome 9p and concurrent deletion of PAX5 and INK4A genes were frequently detected in B-cell linage ALL. PAX5 gene may behave as a tumor suppressor gene during early development of B-cells and its alteration by either fusion to another gene, point mutation, or deletion may be associated with leukemogenesis of B-cell lineage ALL.

scholarly journals P53 and the Carcinoma of the Breast: A Review

2020 ◽  
Vol 3 (1) ◽  
pp. 97-102
Author(s):  
Sujan Narayan Agrawal ◽  
Anuradha Nayak
Keyword(s):  
Target Genes ◽  
Dna Recombination ◽  
Tp53 Gene ◽  
P53 Mutation ◽  
Dominant Negative ◽  
Chromosome Band ◽  
Breast Cancers ◽  
Loss Of Function ◽  
P53 Family ◽  
Regulatory Pathways

TP53 is a gene and p53 is its product protein. Since its discovery many studies have looked into its function and its role in cancer. It is not   only involved in the induction of apoptosis but is also, a key player, in cell cycle regulation, development, differentiation, gene amplification, DNA recombination, chromosomal segregation and cellular senescence and so, it is called “the guardian of genome”. The human TP53 gene spans 20kb on chromosome band 17p13.1. The biological functions of p53 are apoptosis, senescence and cell migration. The evolution of a normal cell towards a cancerous one is a complex process. Tumorogenesis is considered to endow, the evolving tumor with, self-sufficiency of growth signals, insensitivity to antigrowth signals, evasion from programmed cell death, unlimited replicative potentials and finally the ability to invade and metastasize. TP53 may be considered as the “ultimate tumor suppressor gene”. Its oncogenic activity is attributed to loss of function, dominant negative (DN) oncogenic properties and activities of mutant p53. In breast cancer its oncogenic function is due to p53 mutation, changes in- upstream regulatory pathways, in p53 transcriptional target genes, in p53 co-activators, and/or involvement of other family members of p53 family like p63 and p73. The p53 mutation is present in only in about 20% of breast cancers, but when present, they entail the worst prognosis. This interesting paper is a review and discussion about role of p53 in carcinoma breast.

scholarly journals Playing Tag with HIF: The VHL Story

2002 ◽  
Vol 2 (3) ◽  
pp. 131-135 ◽  
Author(s):  
Sherri K. Leung ◽  
Michael Ohh
Keyword(s):  
Ubiquitin Ligase ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
E3 Ubiquitin Ligase ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Matrix Assembly ◽  
Von Hippel Lindau ◽  
Ubiquitin Ligase Complex

Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene product pVHL is the cause of inherited VHL disease and is associated with sporadic kidney cancer. pVHL is found in a multiprotein complex with elongins B/C, Cul2, and Rbx1 forming an E3 ubiquitin ligase complex called VEC. This modular enzyme targets theαsubunits of hypoxia-inducible factor (HIF) for ubiquitin-mediated destruction. Consequently, tumour cells lacking functional pVHL overproduce the products of HIF-target genes such as vascular endothelial growth factor (VEGF), which promotes angiogenesis. This likely accounts for the hypervascular nature of VHL-associated neoplasms. Although pVHL has been linked to the cell-cycle, differentiation, and the regulation of extracellular matrix assembly, microenvironment pH, and tissue invasiveness, this review will focus on the recent insights into the molecular mechanisms governing the E3 ubiquitin ligase function of VEC.

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.

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