scholarly journals UBE2S promotes cell chemoresistance through PTEN-AKT signaling in hepatocellular carcinoma

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Liang Gui ◽  
Sicai Zhang ◽  
Yongzi Xu ◽  
Hongwei Zhang ◽  
Ying Zhu ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Disease Free Survival ◽  
Hepatocellular Cancer ◽  
Akt Signaling ◽  
Akt Inhibitor ◽  
Large Tumor ◽  
Akt Phosphorylation ◽  
Ubiquitin Conjugating Enzyme ◽  
Conjugating Enzyme

AbstractUbiquitination displays a crucial role in various biological functions, such as protein degradation, signal transduction, and cellular homeostasis. Accumulating evidence has indicated that ubiquitination is essential in cancer progression. Ubiquitin-conjugating enzyme E2S (UBE2S) is a member of ubiquitin-conjugating enzyme family of the ubiquitin system and its role in hepatocellular cancer (HCC) is largely unknown. We investigated the role of UBE2S in HCC and found UBE2S upregulation is relevant with large tumor size, recurrence, and advanced TNM stage, serving as an independent risk factor of overall survival (OS) and disease-free survival (DFS) for HCC patients. We conducted in vitro experiments and found that in HCC cells, UBE2S overexpression increases the resistance to 5-FU and oxaliplatin, while UBE2S knockdown achieves an opposite effect. UBE2S is transcriptionally activated by the binding of FOXM1 to UBE2S promoter, which induces its upregulation and reduces PTEN protein level by promoting PTEN ubiquitination at Lys60 and Lys327 and facilitating AKT phosphorylation. The promotional effect of FOXM1-UBE2S axis on HCC cell chemoresistance is attenuated by allosteric AKT inhibitor, MK2206. In conclusion, our results reveal that UBE2S is a prognostic biomarker for HCC patients, and the FOXM1-UBE2S-PTEN-p-AKT signaling axis might be a promising target for the treatment of HCC.

scholarly journals UBE2C Drives Human Cervical Cancer Progression and Is Positively Modulated by mTOR

Biomolecules ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 37
Author(s):  
An-Jen Chiang ◽  
Chia-Jung Li ◽  
Kuan-Hao Tsui ◽  
Chung Chang ◽  
Yuan-chin Ivan Chang ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Progression ◽  
Cancer Staging ◽  
Cervical Squamous Cell Carcinoma ◽  
Cancer Cell Proliferation ◽  
Gynecological Malignancy ◽  
In Vivo Experiments ◽  
Ubiquitin Conjugating Enzyme

Cervical cancer is a common gynecological malignancy, accounting for 10% of all gynecological cancers. Recently, targeted therapy for cervical cancer has shown unprecedented advantages. Several studies have shown that ubiquitin conjugating enzyme E2 (UBE2C) is highly expressed in a series of tumors, and participates in the progression of these tumors. However, the possible impact of UBE2C on the progression of cervical squamous cell carcinoma (CESC) remains unclear. Here, we carried out tissue microarray analysis of paraffin-embedded tissues from 294 cervical cancer patients with FIGO/TNM cancer staging records. The results indicated that UBE2C was highly expressed in human CESC tissues and its expression was related to the clinical characteristics of CESC patients. Overexpression and knockdown of UBE2C enhanced and reduced cervical cancer cell proliferation, respectively, in vitro. Furthermore, in vivo experiments showed that UBE2C regulated the expression and activity of the mTOR/PI3K/AKT pathway. In summary, we confirmed that UBE2C is involved in the process of CESC and that UBE2C may represent a molecular target for CESC treatment.

scholarly journals Monophosphoryl lipid A induces protection against LPS in medullary thick ascending limb through a TLR4-TRIF-PI3K signaling pathway

2017 ◽  
Vol 313 (1) ◽  
pp. F103-F115 ◽  
Author(s):  
Bruns A. Watts ◽  
Thampi George ◽  
Edward R. Sherwood ◽  
David W. Good
Keyword(s):  
Bacterial Infections ◽  
Lipid A ◽  
Thick Ascending Limb ◽  
Akt Inhibitor ◽  
Erk Activation ◽  
Akt Phosphorylation ◽  
Medullary Thick Ascending Limb ◽  
Monophosphoryl Lipid A ◽  
Monophosphoryl Lipid

Monophosphoryl lipid A (MPLA) is a detoxified derivative of LPS that induces tolerance to LPS and augments host resistance to bacterial infections. Previously, we demonstrated that LPS inhibits [Formula: see text] absorption in the medullary thick ascending limb (MTAL) through a basolateral Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-ERK pathway. Here we examined whether pretreatment with MPLA would attenuate LPS inhibition. MTALs from rats were perfused in vitro with MPLA (1 µg/ml) in bath and lumen or bath alone for 2 h, and then LPS was added to (and MPLA removed from) the bath solution. Pretreatment with MPLA eliminated LPS-induced inhibition of [Formula: see text] absorption. In MTALs pretreated with MPLA plus a phosphatidylinositol 3-kinase (PI3K) or Akt inhibitor, LPS decreased [Formula: see text] absorption. MPLA increased Akt phosphorylation in dissected MTALs. The Akt activation was eliminated by a PI3K inhibitor and in MTALs from TLR4−/−or Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF)−/−mice. The effect of MPLA to prevent LPS inhibition of [Formula: see text] absorption also was TRIF dependent. Pretreatment with MPLA prevented LPS-induced ERK activation; this effect was dependent on PI3K. MPLA alone had no effect on [Formula: see text] absorption, and MPLA pretreatment did not prevent ERK-mediated inhibition of [Formula: see text] absorption by aldosterone, consistent with MPLA's low toxicity profile. These results demonstrate that pretreatment with MPLA prevents the effect of LPS to inhibit [Formula: see text] absorption in the MTAL. This protective effect is mediated directly through MPLA stimulation of a TLR4-TRIF-PI3K-Akt pathway that prevents LPS-induced ERK activation. These studies identify detoxified TLR4-based immunomodulators as novel potential therapeutic agents to prevent or treat renal tubule dysfunction in response to bacterial infections.

scholarly journals GLRX3, a novel cancer stem cell-related secretory biomarker of pancreatic ductal adenocarcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jung Hyun Jo ◽  
Sun A Kim ◽  
Jeong Hoon Lee ◽  
Yu Rang Park ◽  
Chanyang Kim ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Progression ◽  
Biomarker Discovery ◽  
Disease Free Survival ◽  
Tumor Formation ◽  
Ductal Adenocarcinoma ◽  
Curative Surgery ◽  
In Vitro Proliferation

Abstract Background Cancer stem cells (CSCs) are implicated in carcinogenesis, cancer progression, and recurrence. Several biomarkers have been described for pancreatic ductal adenocarcinoma (PDAC) CSCs; however, their function and mechanism remain unclear. Method In this study, secretome analysis was performed in pancreatic CSC-enriched spheres and control adherent cells for biomarker discovery. Glutaredoxin3 (GLRX3), a novel candidate upregulated in spheres, was evaluated for its function and clinical implication. Results PDAC CSC populations, cell lines, patient tissues, and blood samples demonstrated GLRX3 overexpression. In contrast, GLRX3 silencing decreased the in vitro proliferation, migration, clonogenicity, and sphere formation of cells. GLRX3 knockdown also reduced tumor formation and growth in vivo. GLRX3 was found to regulate Met/PI3K/AKT signaling and stemness-related molecules. ELISA results indicated GLRX3 overexpression in the serum of patients with PDAC compared to that in healthy controls. The sensitivity and specificity of GLRX3 for PDAC diagnosis were 80.0 and 100%, respectively. When GLRX3 and CA19–9 were combined, sensitivity was significantly increased to 98.3% compared to that with GLRX3 or CA19–9 alone. High GLRX3 expression was also associated with poor disease-free survival in patients receiving curative surgery. Conclusion Overall, these results indicate GLRX3 as a novel diagnostic marker and therapeutic target for PDAC targeting CSCs.

scholarly journals OTUB1 non-catalytically stabilizes the E2 ubiquitin-conjugating enzyme UBE2E1 by preventing its autoubiquitination

2018 ◽  
Vol 293 (47) ◽  
pp. 18285-18295 ◽  
Author(s):  
Nagesh Pasupala ◽  
Marie E. Morrow ◽  
Lauren T. Que ◽  
Barbara A. Malynn ◽  
Averil Ma ◽  
...  
Keyword(s):  
Polyubiquitin Chains ◽  
Protein Ubiquitination ◽  
Ubiquitin Conjugating Enzyme ◽  
Conjugating Enzymes ◽  
E2 Enzymes ◽  
Ubiquitin Conjugating Enzymes ◽  
In Cells ◽  
Conjugating Enzyme

OTUB1 is a deubiquitinating enzyme that cleaves Lys-48–linked polyubiquitin chains and also regulates ubiquitin signaling through a unique, noncatalytic mechanism. OTUB1 binds to a subset of E2 ubiquitin-conjugating enzymes and inhibits their activity by trapping the E2∼ubiquitin thioester and preventing ubiquitin transfer. The same set of E2s stimulate the deubiquitinating activity of OTUB1 when the E2 is not charged with ubiquitin. Previous studies have shown that, in cells, OTUB1 binds to E2-conjugating enzymes of the UBE2D (UBCH5) and UBE2E families, as well as to UBE2N (UBC13). Cellular roles have been identified for the interaction of OTUB1 with UBE2N and members of the UBE2D family, but not for interactions with UBE2E E2 enzymes. We report here a novel role for OTUB1–E2 interactions in modulating E2 protein ubiquitination. We observe that Otub1−/− knockout mice exhibit late-stage embryonic lethality. We find that OTUB1 depletion dramatically destabilizes the E2-conjugating enzyme UBE2E1 (UBCH6) in both mouse and human OTUB1 knockout cell lines. Of note, this effect is independent of the catalytic activity of OTUB1, but depends on its ability to bind to UBE2E1. We show that OTUB1 suppresses UBE2E1 autoubiquitination in vitro and in cells, thereby preventing UBE2E1 from being targeted to the proteasome for degradation. Taken together, we provide evidence that OTUB1 rescues UBE2E1 from degradation in vivo.

Cxcl10 chemokine induces migration of ING4-deficient breast cancer cells via a novel crosstalk mechanism between the Cxcr3 and Egfr receptors

2021 ◽  
Author(s):  
Emily Tsutsumi ◽  
Jeremiah Stricklin ◽  
Emily A. Peterson ◽  
Joyce A. Schroeder ◽  
Suwon Kim
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Disease Free Survival ◽  
Intact Cells ◽  
Free Survival ◽  
Egfr Receptors

The chemokine Cxcl10 has been associated with poor prognosis in breast cancer, but the mechanism is not well understood. Our previous study have shown that CXCL10 was repressed by the ING4 tumor suppressor, suggesting a potential inverse functional relationship. We thus investigated a role for Cxcl10 in the context of ING4 deficiencies in breast cancer. We first analyzed public gene expression datasets and found that patients with CXCL10 -high/ ING4 -low expressing tumors had significantly reduced disease-free survival in breast cancer. In vitro , Cxcl10 induced migration of ING4 -deleted breast cancer cells, but not of ING4 -intact cells. Using inhibitors, we found that Cxcl10-induced migration of ING4 -deleted cells required Cxcr3, Egfr, and the Gβγ subunits downstream of Cxcr3, but not Gαi. Immunofluorescent imaging showed that Cxcl10 induced early transient colocalization between Cxcr3 and Egfr in both ING4 -intact and ING4 -deleted cells, which recurred only in ING4 -deleted cells. A peptide agent that binds to the internal juxtamembrane domain of Egfr inhibited Cxcr3/Egfr colocalization and cell migration. Taken together, these results presented a novel mechanism of Cxcl10 that elicits migration of ING4 -deleted cells, in part by inducing a physical or proximal association between Cxcr3 and Egfr and signaling downstream via Gβγ. These results further indicated that ING4 plays a critical role in the regulation of Cxcl10 signaling that enables breast cancer progression.

scholarly journals Recombinant ubiquitin-conjugating enzyme of Eimeria maxima induces immunogenic maturation in chicken splenic-derived dendritic cells and drives Th1 polarization in-vitro

2020 ◽  
Vol 143 ◽  
pp. 104162
Author(s):  
Shakeel Ahmed Lakho ◽  
Muhammad Haseeb ◽  
Jianmei Huang ◽  
Muhammad Waqqas Hasan ◽  
Muhammad Ali-ul-Husnain Naqvi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Eimeria Maxima ◽  
Ubiquitin Conjugating Enzyme ◽  
Th1 Polarization ◽  
Conjugating Enzyme

scholarly journals Phosphorylated AKT preserves stallion sperm viability and motility by inhibiting caspases 3 and 7

Reproduction ◽  
2014 ◽  
Vol 148 (2) ◽  
pp. 221-235 ◽  
Author(s):  
Juan M Gallardo Bolaños ◽  
Carolina M Balao da Silva ◽  
Patricia Martín Muñoz ◽  
Antolín Morillo Rodríguez ◽  
María Plaza Dávila ◽  
...  
Keyword(s):  
Critical Role ◽  
Membrane Integrity ◽  
Specific Inhibitor ◽  
Akt Inhibitor ◽  
Akt Phosphorylation ◽  
Mitochondrial Superoxide ◽  
Phosphorylated Akt ◽  
Sperm Survival

AKT, also referred to as protein kinase B (PKB or RAC), plays a critical role in controlling cell survival and apoptosis. To gain insights into the mechanisms regulating sperm survival after ejaculation, the role of AKT was investigated in stallion spermatozoa using a specific inhibitor and a phosphoflow approach. Stallion spermatozoa were washed and incubated in Biggers–Whitten–Whittingham medium, supplemented with 1% polyvinyl alcohol (PVA) in the presence of 0 (vehicle), 10, 20 or 30 μM SH5, an AKT inhibitor. SH5 treatment reduced the percentage of sperm displaying AKT phosphorylation, with inhibition reaching a maximum after 1 h of incubation. This decrease in phosphorylation was attributable to either dephosphorylation or suppression of the active phosphorylation pathway. Stallion spermatozoa spontaneously dephosphorylated during in vitro incubation, resulting in a lack of a difference in AKT phosphorylation between the SH5-treated sperm and the control after 4 h of incubation. AKT inhibition decreased the proportion of motile spermatozoa (total and progressive) and the sperm velocity. Similarly, AKT inhibition reduced membrane integrity, leading to increased membrane permeability and reduced the mitochondrial membrane potential concomitantly with activation of caspases 3 and 7. However, the percentage of spermatozoa exhibiting oxidative stress, the production of mitochondrial superoxide radicals, DNA oxidation and DNA fragmentation were not affected by AKT inhibition. It is concluded that AKT maintains the membrane integrity of ejaculated stallion spermatozoa, presumably by inhibiting caspases 3 and 7, which prevents the progression of spermatozoa to an incomplete form of apoptosis.Free Spanish abstractA Spanish translation of this abstract is freely available at http://www.reproduction-online.org/content/148/2/221/suppl/DC1.

scholarly journals Mutations in RAD6, a yeast gene encoding a ubiquitin-conjugating enzyme, stimulate retrotransposition.

1990 ◽  
Vol 10 (3) ◽  
pp. 1017-1022 ◽  
Author(s):  
S Picologlou ◽  
N Brown ◽  
S W Liebman
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Fold Increase ◽  
Yeast Gene ◽  
Gene Encoding ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Ubiquitin Conjugating Enzyme ◽  
First Time ◽  
Conjugating Enzyme

The Saccharomyces cerevisiae DNA repair gene RAD6 encodes a ubiquitin-conjugating enzyme which polyubiquitinates histones in vitro. Here we show that mutations in rad6 increase the frequency of transposition of the retrotransposon Ty into the CAN1 and URA3 loci. Using isogenic RAD6 and rad6 strains, we measured a more than 100-fold increase in the spontaneous rate of retrotransposition due to rad6, although there was no increase in the Ty message level. This is the first time that a mutation in a host gene has been shown to result in an increased rate of retrotransposition.

scholarly journals Functional Interaction between Human Herpesvirus 6 Immediate-Early 2 Protein and Ubiquitin-Conjugating Enzyme 9 in the Absence of Sumoylation

2006 ◽  
Vol 80 (20) ◽  
pp. 10218-10228 ◽  
Author(s):  
Andru Tomoiu ◽  
Annie Gravel ◽  
Robert M. Tanguay ◽  
Louis Flamand
Keyword(s):  
Human Herpesvirus ◽  
Immediate Early ◽  
Human Herpesvirus 6 ◽  
Interacting Protein ◽  
Ubiquitin Conjugating Enzyme ◽  
Herpesvirus 6 ◽  
Transcriptional Complex ◽  
Conjugating Enzyme

ABSTRACT The immediate-early 2 (IE2) protein of human herpesvirus 6 is a potent transactivator of cellular and viral promoters. To better understand the biology of IE2, we generated a LexA-IE2 fusion protein and screened, using the yeast two-hybrid system, a Jurkat T-cell cDNA library for proteins that could interact with IE2. The most frequently isolated IE2-interacting protein was the human ubiquitin-conjugating enzyme 9 (Ubc9), a protein involved in the small ubiquitin-like modifier (SUMO) conjugation pathway. Using deletion mutants of IE2, we mapped the IE2-Ubc9-interacting region to residues 989 to 1037 of IE2. The interaction was found to be of functional significance to IE2, as Ubc9 overexpression significantly repressed promoter activation by IE2. The C93S Ubc9 mutant exhibited a similar effect on IE2, indicating that the E2 SUMO-conjugating function of Ubc9 is not required for its repressive action on IE2. No consensus sumoylation sites or evidence of IE2 conjugation to SUMO could be demonstrated under in vivo or in vitro conditions. Moreover, expression levels and nuclear localization of IE2 were not altered by Ubc9 overexpression, suggesting that Ubc9's repressive function likely occurs at the transcriptional complex level. Overall, our results indicate that Ubc9 influences IE2's function and provide new information on the complex interactions that occur between herpesviruses and the sumoylation pathway.

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