scholarly journals The Role of Nonerythroid SpectrinαII in Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Anne Ackermann ◽  
Angela Brieger
Keyword(s):  
Dna Repair ◽  
Current Knowledge ◽  
Tumor Development ◽  
Therapy Response ◽  
Cell Contact ◽  
Altered Expression ◽  
Potential Marker ◽  
Specific Regulation ◽  
And Migration

Nonerythroid spectrinαII (SPTAN1) is an important cytoskeletal protein that ensures vital cellular properties including polarity and cell stabilization. In addition, it is involved in cell adhesion, cell-cell contact, and apoptosis. The detection of altered expression of SPTAN1 in tumors indicates that SPTAN1 might be involved in the development and progression of cancer. SPTAN1 has been described in cancer and therapy response and proposed as a potential marker protein for neoplasia, tumor aggressiveness, and therapeutic efficiency. On one hand, the existing data suggest that overexpression of SPTAN1 in tumor cells reflects neoplastic and tumor promoting activity. On the other hand, nuclear SPTAN1 can have tumor suppressing effects by enabling DNA repair through interaction with DNA repair proteins. Moreover, SPTAN1 cleavage products occur during apoptosis and could serve as markers for the efficacy of cancer therapy. Due to SPTAN1’s multifaceted functions and its role in adhesion and migration, SPTAN1 can influence tumor growth and progression in both positive and negative directions depending on its specific regulation. This review summarizes the current knowledge on SPTAN1 in cancer and depicts several mechanisms by which SPTAN1 could impact tumor development and aggressiveness.

scholarly journals DYRK1A regulates the recruitment of 53BP1 to the sites of DNA damage in part through interaction with RNF169

2018 ◽  
Author(s):  
Vijay R. Menon ◽  
Varsha Ananthapadmanabhan ◽  
Selene Swanson ◽  
Siddharth Saini ◽  
Fatmata Sesay ◽  
...  
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Therapy Response ◽  
Strand Break ◽  
Dependent Manner ◽  
Dsb Repair ◽  
Altered Expression ◽  
Developmental Abnormalities

SummaryHumanDYRK1Agene encoding Dual-specificity tyrosine (Y)- Regulated Kinase 1A (DYRK1A) is a dosage-dependent gene whereby either trisomy or haploinsufficiency result in developmental abnormalities. However, the function and regulation of this important protein kinase are not fully understood. Here we report proteomic analysis of DYRK1A in human cells that revealed a novel role of DYRK1A in the DNA double-strand break (DSB) repair signaling. This novel function of DYRK1A is mediated in part by its interaction with ubiquitin-binding protein RNF169 that regulates the choice between homologous recombination (HR) and non-homologous end joining (NHEJ) DSB repair. Accumulation of RNF169 at the DSB sites promotes homologous recombination (HR) by limiting the recruitment of the scaffold protein 53BP1 that promotes NHEJ by protecting the DNA ends from resection. Inducible overexpression of active, but not the kinase inactive, DYRK1A in U-2 OS cells inhibited accumulation of 53BP1 at the DSB sites in RNF169-dependent manner. Mutation of DYRK1A phosphorylation sites in RNF169 or pharmacological inhibition of DYRK1A using harmine decreased the ability of RNF169 to displace 53BP1 from radiation-induced DSB sites. In order to further investigate the role of DYRK1A in regulation of DNA repair, we used CRISPR-Cas9 mediated knockout of DYRK1A in human and mouse cells. Interestingly, knockout of DYRK1A also caused a defect in 53BP1 DSB recruitment that was independent of RNF169, suggesting that dosage of DYRK1A can influence the DNA repair processes through several mechanisms. U-2 OS cells devoid of DYRK1A displayed an increased DNA repair and HR efficiency, and showed a decreased sensitivity to the PARP inhibitor olaparib when compared to control cells. Given evidence of its altered expression in human cancers, DYRK1A levels could represent a significant determinant of the DNA damaging therapy response.

scholarly journals Role of Extracellular Matrix in Gastrointestinal Cancer-Associated Angiogenesis

2020 ◽  
Vol 21 (10) ◽  
pp. 3686 ◽  
Author(s):  
Eva Andreuzzi ◽  
Alessandra Capuano ◽  
Evelina Poletto ◽  
Eliana Pivetta ◽  
Albina Fejza ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Progression ◽  
Cell Function ◽  
Current Knowledge ◽  
Tumor Development ◽  
Therapy Response ◽  
Therapeutic Approaches ◽  
Endothelial Cell Function ◽  
New Therapeutic Approaches

Gastrointestinal tumors are responsible for more cancer-related fatalities than any other type of tumors, and colorectal and gastric malignancies account for a large part of these diseases. Thus, there is an urgent need to develop new therapeutic approaches to improve the patients’ outcome and the tumor microenvironment is a promising arena for the development of such treatments. In fact, the nature of the microenvironment in the different gastrointestinal tracts may significantly influence not only tumor development but also the therapy response. In particular, an important microenvironmental component and a potential therapeutic target is the vasculature. In this context, the extracellular matrix is a key component exerting an active effect in all the hallmarks of cancer, including angiogenesis. Here, we summarized the current knowledge on the role of extracellular matrix in affecting endothelial cell function and intratumoral vascularization in the context of colorectal and gastric cancer. The extracellular matrix acts both directly on endothelial cells and indirectly through its remodeling and the consequent release of growth factors. We envision that a deeper understanding of the role of extracellular matrix and of its remodeling during cancer progression is of chief importance for the development of new, more efficacious, targeted therapies.

scholarly journals Glutathione S - transferases class Pi and Mi and their significance in oncology

2017 ◽  
Vol 71 (1) ◽  
pp. 0-0 ◽  
Author(s):  
Zofia Marchewka ◽  
Agnieszka Piwowar ◽  
Sylwia Ruzik ◽  
Anna Długosz
Keyword(s):  
Redox Homeostasis ◽  
Current Data ◽  
Altered Expression ◽  
Potential Marker ◽  
Inflammatory Processes ◽  
Glutathione S Transferases ◽  
Endogenous Substrates ◽  
Cancer Tissues ◽  
Serum And Urine

In this article the current data, which shows that glutathione S-transferases (GST) class Pi and Mi are interesting and promising biomarkers in acute and chronic inflammatory processes as well as in the oncology, were presented based on the review of the latest experimental and clinical studies. The article shows their characteristics, functions and participation (direct - GST Pi, indirect - GST Mi) in the regulation of signaling pathways of JNK kinases, which are involved in cell differentiation. Overexpression of glutathione S-transferases class Pi and Mi in many cancer cells plays a key role in cancer treatment, making them resistant to chemotherapy. GST isoenzymes are involved in the metabolism of various types of xenobiotics and endogenous substrates, so their altered expression in cancer tissues as well as in serum and urine could be an important potential marker of the cancer and an indicator of oxidative stress. The study shows the role of glutathione S-transferases in redox homeostasis of tumor cells and in the mechanism of resistance to anticancer drugs.

scholarly journals Engagement of the CXCL12–CXCR4 Axis in the Interaction of Endothelial Progenitor Cell and Smooth Muscle Cell to Promote Phenotype Control and Guard Vascular Homeostasis

2022 ◽  
Vol 23 (2) ◽  
pp. 867
Author(s):  
Sebastian F. Mause ◽  
Elisabeth Ritzel ◽  
Annika Deck ◽  
Felix Vogt ◽  
Elisa A. Liehn
Keyword(s):  
Smooth Muscle ◽  
Feedback Loop ◽  
Cell Contact ◽  
Endothelial Progenitor ◽  
Vascular Homeostasis ◽  
Relevant Role ◽  
Direct Cell ◽  
And Migration ◽  
Cxcr4 Axis

Endothelial progenitor cells (EPCs) are involved in vascular repair and modulate properties of smooth muscle cells (SMCs) relevant for their contribution to neointima formation following injury. Considering the relevant role of the CXCL12–CXCR4 axis in vascular homeostasis and the potential of EPCs and SMCs to release CXCL12 and express CXCR4, we analyzed the engagement of the CXCL12–CXCR4 axis in various modes of EPC–SMC interaction relevant for injury- and lipid-induced atherosclerosis. We now demonstrate that the expression and release of CXCL12 is synergistically increased in a CXCR4-dependent mechanism following EPC–SMC interaction during co-cultivation or in response to recombinant CXCL12, thus establishing an amplifying feedback loop Additionally, mechanical injury of SMCs induces increased release of CXCL12, resulting in enhanced CXCR4-dependent recruitment of EPCs to SMCs. The CXCL12–CXCR4 axis is crucially engaged in the EPC-triggered augmentation of SMC migration and the attenuation of SMC apoptosis but not in the EPC-mediated increase in SMC proliferation. Compared to EPCs alone, the alliance of EPC–SMC is superior in promoting the CXCR4-dependent proliferation and migration of endothelial cells. When direct cell–cell contact is established, EPCs protect the contractile phenotype of SMCs via CXCL12–CXCR4 and reverse cholesterol-induced transdifferentiation toward a synthetic, macrophage-like phenotype. In conclusion we show that the interaction of EPCs and SMCs unleashes a CXCL12–CXCR4-based autoregulatory feedback loop promoting regenerative processes and mediating SMC phenotype control to potentially guard vascular homeostasis.

scholarly journals Arabidopsis Mediator subunit 17 connects transcription with DNA repair after UV-B exposure

2021 ◽  
Author(s):  
Marisol Giustozzi ◽  
Santiago Freytes ◽  
Aime Jaskolowski ◽  
Micaela Lichy ◽  
Julieta L. Mateos ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Transcription Initiation ◽  
Plant Responses ◽  
Repair System ◽  
Root Tips ◽  
Direct Role ◽  
Altered Expression ◽  
Eukaryotic Organisms

Mediator 17 (MED17) is a subunit of the Mediator complex that regulates transcription initiation in eukaryotic organisms. In yeast and humans, MED17 also participates in DNA repair, physically interacting with proteins of the Nucleotide Excision DNA Repair system. We here analyzed the role of MED17 in Arabidopsis plants exposed to UV-B radiation, which role has not been previously described. Comparison of med17 mutant transcriptome to that of WT plants showed that almost one third of transcripts with altered expression in med17 plants are also changed by UV-B exposure in WT plants. To validate the role of MED17 in UV-B irradiated plants, plant responses to UV-B were analyzed, including flowering time, DNA damage accumulation and programmed cell death in the meristematic cells of the root tips. Our results show that med17 and OE MED17 plants have altered responses to UV-B; and that MED17 participates in various aspects of the DNA damage response (DDR). Increased sensitivity to DDR after UV-B in med17 plants can be due to altered regulation of UV-B responsive transcripts; but additionally MED17 physically interacts with DNA repair proteins, suggesting a direct role of this Mediator subunit during repair. Finally, we here also show that MED17 is necessary to regulate the DDR activated by ATR, and that PDCD5 overexpression reverts the deficiencies in DDR shown in med17 mutants. Together, the data presented demonstrates that MED17 is an important regulator of the DDR after UV-B radiation in Arabidopsis plants.

scholarly journals The Role of Microglia and Matrix Metalloproteinases Involvement in Neuroinflammation and Gliomas

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Helen Könnecke ◽  
Ingo Bechmann
Keyword(s):  
Multiple Sclerosis ◽  
Matrix Metalloproteinases ◽  
Current Knowledge ◽  
Malignant Gliomas ◽  
Therapeutic Strategies ◽  
Glioma Invasion ◽  
Glia Limitans ◽  
And Migration

Matrix metalloproteinases (MMPs) are involved in the pathogenesis of neuroinflammatory diseases (such as multiple sclerosis) as well as in the expansion of malignant gliomas because they facilitate penetration of anatomical barriers (such as the glia limitans) and migration within the neuropil. This review elucidates pathomechanisms and summarizes the current knowledge of the involvement of MMPs in neuroinflammation and glioma, invasion highlighting microglia as major sources of MMPs. The induction of expression, suppression, and multiple pathways of function of MMPs in these scenarios will also be discussed. Understanding the induction and action of MMPs might provide valuable information and reveal attractive targets for future therapeutic strategies.

scholarly journals The Role of Poly(ADP-ribose) Polymerase-1 in Rheumatoid Arthritis

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Samuel García ◽  
Carmen Conde
Keyword(s):  
Rheumatoid Arthritis ◽  
Septic Shock ◽  
Dna Repair ◽  
Beneficial Effect ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Genomic Stability ◽  
Inflammatory Processes ◽  
Parp 1

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme with a crucial role in the maintenance of genomic stability. In addition to the role of PARP-1 in DNA repair, multiple studies have also demonstrated its involvement in several inflammatory diseases, such as septic shock, asthma, atherosclerosis, and stroke, as well as in cancer. In these diseases, the pharmacological inhibition of PARP-1 has shown a beneficial effect, suggesting that PARP-1 regulates their inflammatory processes. In recent years, we have studied the role of PARP-1 in rheumatoid arthritis, as have other researchers, and the results have shown that PARP-1 has an important function in the development of this disease. This review summarizes current knowledge on the effects of PARP-1 in rheumatoid arthritis.

Role of DNA repair systems in malignant tumor development in the elderly

2008 ◽  
Vol 8 (2) ◽  
pp. 65-72 ◽  
Author(s):  
Tomio Arai ◽  
Motoji Sawabe ◽  
Takayuki Hosoi ◽  
Noriko Tanaka
Keyword(s):  
Dna Repair ◽  
Malignant Tumor ◽  
Tumor Development ◽  
The Elderly ◽  
Repair Systems

scholarly journals Na+/Ca2+ exchangers regulate the migration and proliferation of human gastric myofibroblasts

2013 ◽  
Vol 305 (8) ◽  
pp. G552-G563 ◽  
Author(s):  
Lajos V. Kemény ◽  
Andrea Schnúr ◽  
Mátyás Czepán ◽  
Zoltán Rakonczay ◽  
Eleonóra Gál ◽  
...  
Keyword(s):  
Tumor Development ◽  
Oscillatory Activity ◽  
Pcr Analysis ◽  
Gastric Diseases ◽  
Protein Levels ◽  
Intracellular Ca ◽  
Transitional Cells ◽  
And Migration ◽  
Proliferation And Migration

Gastrointestinal myofibroblasts are contractile, electrically nonexcitable, transitional cells that play a role in extracellular matrix production, in ulcer healing, and in pathophysiological conditions they contribute to chronic inflammation and tumor development. Na+/Ca2+ exchangers (NCX) are known to have a crucial role in Ca2+ homeostasis of contractile cells, however, no information is available concerning the role of NCX in the proliferation and migration of gastrointestinal myofibroblasts. In this study, our aim was to investigate the role of NCX in the Ca2+ homeostasis, migration, and proliferation of human gastrointestinal myofibroblasts, focusing on human gastric myofibroblasts (HGMs). We used microfluorometric measurements to investigate the intracellular Ca2+ and Na+ concentrations, PCR analysis and immunostaining to show the presence of the NCX, patch clamp for measuring NCX activity, and proliferation and migration assays to investigate the functional role of the exchanger. We showed that 53.0 ± 8.1% of the HGMs present Ca2+ oscillations, which depend on extracellular Ca2+ and Na+, and can be inhibited by NCX inhibitors. NCX1, NCX2, and NCX3 were expressed at both mRNA and protein levels in HGMs, and they contribute to the intracellular Ca2+ and Na+ homeostasis as well, regardless of the oscillatory activity. NCX inhibitors significantly blocked the basal and insulin-like growth factor II-stimulated migration and proliferation rates of HGMs. In conclusion, we showed that NCX plays a pivotal role in regulating the Ca2+ homeostasis, migration, and proliferation of HGMs. The inhibition of NCX activity may be a potential therapeutic target in hyperproliferative gastric diseases.

Deciphering the Role of Glutamate Signaling in Glioblastoma Multiforme: Current Therapeutic Modalities and Future Directions

2020 ◽  
Vol 26 (37) ◽  
pp. 4777-4788 ◽  
Author(s):  
Hamid Mollazadeh ◽  
Elmira Mohtashami ◽  
Seyed H. Mousavi ◽  
Mohammad Soukhtanloo ◽  
Mohammad M. Vahedi ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Current Knowledge ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Invasion And Migration ◽  
Glutamate Signaling ◽  
Therapeutic Modalities ◽  
Glutamatergic Signaling ◽  
And Migration

As the most popular intrinsic neoplasm throughout the brain, glioblastoma multiforme (GBM) is resistant to existing therapies. Due to its invasive nature, GBM shows a poor prognosis despite aggressive surgery and chemoradiation. Therefore, identifying and understanding the critical molecules of GBM can help develop new therapeutic strategies. Glutamatergic signaling dysfunction has been well documented in neurodegenerative diseases as well as in GBM. Inhibition of glutamate receptor activation or extracellular glutamate release by specific antagonists inhibits cell development, invasion, and migration and contributes to apoptosis and autophagy in GBM cells. This review outlines the current knowledge of glutamate signaling involvement and current therapeutic modalities for the treatment of GBM.

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