scholarly journals Post-transcriptional screen of cancer amplified genes identifies ERBB2/Her2 signaling as AU-rich mRNA stability-promoting pathway

Oncogenesis ◽  
2021 ◽  
Vol 10 (9) ◽  
Author(s):  
Jenan Al-Matouq ◽  
Latifa Al-Haj ◽  
Maher Al-Saif ◽  
Khalid S. A. Khabar
Keyword(s):  
Transcriptional Control ◽  
Mrna Decay ◽  
Ectopic Expression ◽  
Hek293 Cells ◽  
Her2 Overexpression ◽  
Cancer Genes ◽  
Mediated Effects ◽  
Inactive Form ◽  
Her2 Signaling ◽  
The Impact

AbstractAmplification of specific cancer genes leads to their over-expression contributing to tumor growth, spread, and drug resistance. Little is known about the ability of these amplified oncogenes to augment the expression of cancer genes through post-transcriptional control. The AU-rich elements (ARE)-mediated mRNA decay is compromised for many key cancer genes leading to their increased abundance and effects. Here, we performed a post-transcriptional screen for frequently amplified cancer genes demonstrating that ERBB2/Her2 overexpression was able to augment the post-transcriptional effects. The ERBB1/2 inhibitor, lapatinib, led to the reversal of the aberrant ARE-mediated process in ERBB2-amplified breast cancer cells. The intersection of overexpressed genes associated with ERBB2 amplification in TCGA datasets with ARE database (ARED) identified ERBB2-associated gene cluster. Many of these genes were over-expressed in the ERBB2-positive SKBR3 cells compared to MCF10A normal-like cells, and were under-expressed due to ERBB2 siRNA treatment. Lapatinib accelerated the ARE-mRNA decay for several ERBB2-regulated genes. The ERBB2 inhibitor decreased both the abundance and stability of the phosphorylated inactive form of the mRNA decay-promoting protein, tristetraprolin (ZFP36/TTP). The ERBB2 siRNA was also able to reduce the phosphorylated ZFP36/TTP form. In contrast, ectopic expression of ERBB2 in MCF10A or HEK293 cells led to increased abundance of the phosphorylated ZFP36/TTP. The effect of ERBB2 on TTP phosphorylation appeared to be mediated via the MAPK-MK2 pathway. Screening for the impact of other amplified cancer genes in HEK293 cells also demonstrated that EGFR, AKT2, CCND1, CCNE1, SKP2, and FGFR3 caused both increased abundance of phosphorylated ZFP36/TTP and ARE-post-transcriptional reporter activity. Thus, specific amplified oncogenes dysregulate post-transcriptional ARE-mediated effects, and targeting the ARE-mediated pathway itself may provide alternative therapeutic approaches.

scholarly journals The agonist of JWA gene JAC1 suppresses proliferation of breast cancer through JWA/p38/SMURF1/HER2 signaling

2020 ◽  
Author(s):  
Yanlin Ren ◽  
Dongyin Chen ◽  
Junjie Chen ◽  
Zurong Zhai ◽  
Aiping Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Her2 Overexpression ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Her2 Signaling ◽  
The Impact ◽  
Positive Breast Cancer

Abstract Background The HER2-positive breast cancer accounts for 20-30% of all breast cancers. The overexpression of HER2 is associated with malignant proliferation and invasiveness in several cancers. Some HER2 targeting drugs are widely used in clinic to block HER2 or its tyrosine kinase and improve the prognosis of patients. However, drug resistance and side effects are still a big challenge worldwide. Our previous studies have demonstrated that JWA down-regulates HER2 expression and inhibits cell proliferation and migration in gastric cancer cells. Methods The association of JWA with HER2 were analyzed by IHC in 90 tumor sample tissues and paired non-cancerous adjacent normal tissues. The impact of JAC1 on HER2-positive breast cancer cells was studied using colony formation assay. The effect of JAC1 on the localization of HER2 was detected by immunofluorescence microscopy assay. Western blotting, RT-PCR and immunoprecipitation assay were utilized to investigate the mechanisms of JWA regulating HER2. Finally, xenograft mouse models using BT474 cells were established to confirm the effect of JAC1 on tumor growth. Results In this study, we found that JAC1, a small molecule agonist of JWA gene, dose-dependently suppressed HER2-positive breast cancer proliferation in vitro and in vivo . Importantly, the inhibitory roles of JAC1 was due to the degradation of HER2 overexpression. The mechanistic evidences showed JAC1 increased the ubiquitination of HER2 at the K716 through the E3 ubiquitin ligase SMURF1; further, the activation of SMURF1 was due to reduced expression of NEDD4, an E3 ubiquitin ligase for SMURF1. Finally, we identified that the role of JAC1 on NEDD4 was realized through JWA-p38-GATA-1-NEDD4 axis. Conclusions These findings suggest that JAC1 may as a novel therapeutic agent to breast cancer through JWA/p38/GATA-1/NEDD4/SMURF1/HER2 signaling axis.

scholarly journals Calcium phosphate phase transition in the presence of Aminosilane

2014 ◽  
Vol 70 (a1) ◽  
pp. C67-C67
Author(s):  
Babak Mostaghaci ◽  
Brigitta Loretz ◽  
Robert Haberkorn ◽  
Guido Kickelbick ◽  
Claus-Michael Lehr
Keyword(s):  
Phase Transition ◽  
Calcium Phosphate ◽  
Blood Compatibility ◽  
Transfection Efficiency ◽  
Hek293 Cells ◽  
Step Method ◽  
Calcium Phosphate Nanoparticles ◽  
Amine Groups ◽  
The Impact

Calcium phosphate has been the point of interest for in vitro gene delivery for many years because of its biocompatibility and straight forward application. However, there are some limitations regarding in vivo administration of these particles mostly because of vast agglomeration of the particles and lack of strong bond between the particles and pDNA. We introduced a simple single step method to functionalize calcium phosphate nanoparticles with Aminosilanes having a different number of amine groups. The nanoparticles were characterized chemically and structurally and their toxicity and interaction with pDNA were studied as well. Results revealed that different crystalline phase of calcium phosphate nanoparticles (Brushite and Hydroxyapatite) with a size below 150 nm were prepared, depending on conditions of synthesis and phase, each with a narrow size distribution. The aminosilane agents caused oriented nucleation and growth of crystallites and can decrease the pH for producing hydroxyapatite phase. The phenomenon could be revealed with the presence of anisotropy in the structure of synthesized hydroxyapatite. The number of amine groups in the Aminosilane agent could change the phase transition pH. Brushite particles revealed to have stronger interaction with pDNA mostly because of their higher positive surface charge. Both particles showed blood compatibility and negligible toxicity. Transfection experiment revealed the capability of both brushite and hydroxyapatite particles to transfect A549 and HEK293 cells. The new modified nanoparticles can be stored in a dried state and re-dispersed easily at the time of administration. Moreover, the transfection efficiency is higher in comparison with conventional calcium phosphate. This study showed the impact of presence and type of the modifying agent on the crystal structure and the amount of surface functionalization of nanoparticles, which in consequence influenced their interaction with cells.

scholarly journals Functional antagonism of chromatin modulators regulates epithelial-mesenchymal transition

2021 ◽  
Vol 7 (9) ◽  
pp. eabd7974
Author(s):  
Michela Serresi ◽  
Sonia Kertalli ◽  
Lifei Li ◽  
Matthias Jürgen Schmitt ◽  
Yuliia Dramaretska ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Developmental Process ◽  
Epithelial Mesenchymal Transition ◽  
Chromatin Remodelers ◽  
Mesenchymal Transition ◽  
Signature Genes ◽  
Chromatin Regulators ◽  
The Impact

Epithelial-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to modulate proliferation, migration, and stress response. Whereas kinase signaling is believed to be an EMT driver, the molecular mechanisms underlying epithelial-mesenchymal interconversion are incompletely understood. Here, we show that the impact of chromatin regulators on EMT interconversion is broader than that of kinases. By combining pharmacological modulation of EMT, synthetic genetic tracing, and CRISPR interference screens, we uncovered a minority of kinases and several chromatin remodelers, writers, and readers governing homeostatic EMT in lung cancer cells. Loss of ARID1A, DOT1L, BRD2, and ZMYND8 had nondeterministic and sometimes opposite consequences on epithelial-mesenchymal interconversion. Together with RNAPII and AP-1, these antagonistic gatekeepers control chromatin of active enhancers, including pan-cancer-EMT signature genes enabling supraclassification of anatomically diverse tumors. Thus, our data uncover general principles underlying transcriptional control of cancer cell plasticity and offer a platform to systematically explore chromatin regulators in tumor-state–specific therapy.

Post-transcriptional control via iron-responsive elements: the impact of aberrations in hereditary disease

1999 ◽  
Vol 437 (3) ◽  
pp. 219-230 ◽  
Author(s):  
Wolfgang Mikulits ◽  
Matthias Schranzhofer ◽  
Hartmut Beug ◽  
Ernst W Müllner
Keyword(s):  
Transcriptional Control ◽  
Hereditary Disease ◽  
Iron Responsive Elements ◽  
The Impact

The Impact of Variants at Branchpoint Splicing Elements in Cancer Genes

2021 ◽  
Author(s):  
Daffodil  Canson ◽  
Troy Dumenil ◽  
Michael  Parsons ◽  
Tracy  O’Mara ◽  
Aimee  Davidson ◽  
...  
Keyword(s):  
Cancer Genes ◽  
The Impact

scholarly journals The Impact of Post-transcriptional Control: Better Living Through RNA Regulons

2018 ◽  
Vol 9 ◽  
Author(s):  
Biljana Culjkovic-Kraljacic ◽  
Katherine L. B. Borden
Keyword(s):  
Transcriptional Control ◽  
The Impact

scholarly journals The impact of oncogenic mutations of the viral Src kinase on the structure and stability of the SH3 domain

2021 ◽  
Vol 77 (6) ◽  
Author(s):  
M. Carmen Salinas-Garcia ◽  
Marina Plaza-Garrido ◽  
Ana Camara-Artigas
Keyword(s):  
Tyrosine Kinases ◽  
Src Kinase ◽  
Physiological Role ◽  
Sh3 Domain ◽  
Regulation Mechanism ◽  
Oncogenic Mutations ◽  
Inactive Form ◽  
The Stability ◽  
Cell Growth And Proliferation ◽  
The Impact

Src kinase belongs to the family of Src-related nonreceptor tyrosine kinases. Because of its physiological role in cell growth and proliferation, its activity is strictly controlled by several mechanisms. Nevertheless, in viral Src kinase (v-Src) some of these mechanisms fail, and its uncontrolled activity is responsible for the occurrence of cancer. Here, the crystal structures of three SH3-domain mutants of v-Src were determined to unveil the effects of these oncogenic mutations in this regulatory domain. Mutations in the n-Src and distal loops have a low impact on the overall structure of the domain and its capacity to form intertwined dimers. However, mutations in the RT loop compromise the stability of the domain and make the protein very prone to aggregation. Additionally, these mutations prevent the formation of intertwined dimers. The results show a synergistic effect between mutations in the RT loop and those in the n-Src and distal loops. Analysis of the structures of the v-Src SH3-domain mutants and the closed inactive conformation of cellular Src kinase (c-Src) point to a loss of the interactions that are required to establish the compact inactive form of the kinase. Nevertheless, an analysis of structures of the c-Src SH3 domain complexed with class I and II peptides points to minor changes in the interactions between the v-Src SH3 domain and these peptides. In this way, the structures reported here indicate that mutations in the RT loop might impair the kinase regulation mechanism without affecting the recognition of short proline-rich motifs in the target proteins of the kinase, thus explaining the oncogenic behaviour of the protein.

scholarly journals Hepatitis C Virus Core Protein Suppresses NF-κB Activation and Cyclooxygenase-2 Expression by Direct Interaction with IκB Kinase β

2005 ◽  
Vol 79 (12) ◽  
pp. 7648-7657 ◽  
Author(s):  
Myungsoo Joo ◽  
Young S. Hahn ◽  
Minjae Kwon ◽  
Ruxana T. Sadikot ◽  
Timothy S. Blackwell ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nuclear Translocation ◽  
Core Protein ◽  
Ectopic Expression ◽  
Cyclooxygenase 2 ◽  
Necrosis Factor Alpha ◽  
Iκb Kinase ◽  
Cox 2 ◽  
The Impact

ABSTRACT In addition to hepatocytes, hepatitis C virus (HCV) infects immune cells, including macrophages. However, little is known concerning the impact of HCV infection on cellular functions of these immune effector cells. Lipopolysaccharide (LPS) activates IκB kinase (IKK) signalsome and NF-κB, which leads to the expression of cyclooxygenase-2 (COX-2), which catalyzes production of prostaglandins, potent effectors on inflammation and possibly hepatitis. Here, we examined whether expression of HCV core interferes with IKK signalsome activity and COX-2 expression in activated macrophages. In reporter assays, HCV core inhibited NF-κB activation in RAW 264.7 and MH-S murine macrophage cell lines treated with bacterial LPS. HCV core inhibited IKK signalsome and IKKβ kinase activities induced by tumor necrosis factor alpha in HeLa cells and coexpressed IKKγ in 293 cells, respectively. HCV core was coprecipitated with IΚΚβ and prevented nuclear translocation of IKKβ. NF-κB activation by either LPS or overexpression of IKKβ was sufficient to induce robust expression of COX-2, which was markedly suppressed by ectopic expression of HCV core. Together, these data indicate that HCV core suppresses IKK signalsome activity, which blunts COX-2 expression in macrophages. Additional studies are necessary to determine whether interrupted COX-2 expression by HCV core contributes to HCV pathogenesis.

scholarly journals The Role of Activating Transcription Factor 4 (ATF4) in the Physiological Response to Dietary Sulfur Amino Acid Restriction (OR27-01-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
William Jonsson ◽  
Nicholas Margolies ◽  
Emily Mirek ◽  
Thomas Gettys ◽  
Tracy Anthony
Keyword(s):  
Transcription Factor ◽  
Energy Expenditure ◽  
Transcriptional Control ◽  
Control Diet ◽  
Fibroblast Growth Factor 21 ◽  
Restricted Diet ◽  
Biological Sex ◽  
Funding Sources ◽  
Activating Transcription Factor 4 ◽  
The Impact

Abstract Objectives Dietary restriction of the sulfur amino acids (SAAs) improves metabolic health in part via hepatic production of fibroblast growth factor 21 (FGF21). Transcriptional control of Fgf21includes regulation by ATF4 during low protein feeding. Therefore, we aimed to determine the impact of Atf4 deletion on FGF21 levels and associated metabolic outcomes in mice fed a SAA restricted diet. Methods Male and female mice lacking Atf4 globally or in hepatocytes only were fed either a SAA restricted diet (0.17% Met, 0% Cys) or a control diet (0.86% Met, 0% Cys) alongside littermate controls for up to 10 wk. Body mass and composition, energy expenditure and intake were measured. Blood and tissues were collected at specific time points. Transcript (RT-qPCR) and protein (ELISA and Western blot) abundances were analyzed by two factor ANOVA or Kruskal-Wallis Test, with alpha = 0.05. Results Independent of genotype, SAA restriction attenuated weight gain and reduced adiposity despite increased food intake. Improvements in body weight and composition strongly associated with increased energy expenditure regardless of genotype. Deletion of Atf4 did not prevent hepatic Fgf21 nor circulating FGF21 from increasing during chronic SAA restriction (P < 0.05, effect of diet). However, loss of hepatic Atf4 prevented increased circulating FGF21 at 12 h. Overall, males fed the SAA restricted diet induced hepatic Fgf21and serum FGF21 to a greater degree than females. Other known ATF4 targets in liver such as asparagine synthetase, Asns, showed significant induction in the livers of only intact SAA restricted mice. Conversely, loss of Atf4 exacerbated induction of the pro-apoptotic transcription factor Chop (P < 0.05) by SAA restriction. Conclusions Genetic loss of Atf4 delays but does not impede FGF21 production during dietary SAA restriction. Biological sex is a contributing factor to some of the physiological responses to dietary SAA restriction. Funding Sources DK109714 (TGA) and DK096311 (TWG).

scholarly journals Angiopoietin-2 Combined with Radiochemotherapy Impedes Glioblastoma Recurrence by Acting in an Autocrine and Paracrine Manner: A Preclinical Study

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3585
Author(s):  
Charly Helaine ◽  
Aurélie E. Ferré ◽  
Marine M. Leblond ◽  
Elodie A. Pérès ◽  
Myriam Bernaudin ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Ectopic Expression ◽  
Vascular Tumor ◽  
Preclinical Study ◽  
Raw 264.7 Cells ◽  
Preclinical Model ◽  
Tie2 Receptor ◽  
Angiopoietin 2 ◽  
The Impact

(1) We wanted to assess the impact of Ang2 in RCT-induced changes in the environment of glioblastoma. (2) The effect of Ang2 overexpression in tumor cells was studied in the GL261 syngeneic immunocompetent model of GB in response to fractionated RCT. (3) We showed that RCT combined with Ang2 led to tumor clearance for the GL261-Ang2 group by acting on the tumor cells as well as on both vascular and immune compartments. (4) In vitro, Ang2 overexpression in GL261 cells exposed to RCT promoted senescence and induced robust genomic instability, leading to mitotic death. (5) Coculture experiments of GL261-Ang2 cells with RAW 264.7 cells resulted in a significant increase in macrophage migration, which was abrogated by the addition of soluble Tie2 receptor. (6) Together, these preclinical results showed that, combined with RCT, Ang2 acted in an autocrine manner by increasing GB cell senescence and in a paracrine manner by acting on the innate immune system while modulating the vascular tumor compartment. On this preclinical model, we found that an ectopic expression of Ang2 combined with RCT impedes tumor recurrence.

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