1,720,972 research outputs found
Ataxia-telangiectasia mutated kinase in the control of oxidative stress, mitochondria, and autophagy in cancer: A maestro with a large orchestra
Full text linkAtaxia-telangiectasia mutated kinase (ATM) plays a central role in the DNA damage response (DDR) and mutations in its gene lead to the development of a rare autosomic genetic disorder, ataxia telangiectasia (A-T) characterized by neurodegeneration, premature aging, defects in the immune response, and higher incidence of lymphoma development. The ability of ATM to control genome stability several pointed to ATM as tumor suppressor gene. Growing evidence clearly support a significant role of ATM, in addition to its master ability to control the DDR, as principle modulator of oxidative stress response and mitochondrial homeostasis, as well as in the regulation of autophagy, hypoxia, and cancer stem cell survival. Consistently, A-T is strongly characterized by aberrant oxidative stress, significant inability to remove damaged organelles such as mitochondria. These findings raise the question whether ATM may contribute to a more general hijack of signaling networks in cancer, therefore, playing a dual role in this context. Indeed, an unexpected tumorigenic role for ATM, in particular, tumor contexts has been demonstrated. Genetic inactivation of Beclin-1, an autophagy regulator, significantly reverses mitochondrial abnormalities and tumor development in ATM-null mice, independently of DDR. Furthermore, ATM sustains cancer stem cells survival by promoting the autophagic flux and ATM kinase activity is enhanced in HER2-dependent tumors. This mini-review aims to shed new light on the complexity of these new molecular circuits through which ATM may modulate cancer progression and to highlight a novel role of ATM in the control of proteostasis
ATM Kinase-Dependent Regulation of Autophagy: A Key Player in Senescence?
No full textIncreasing evidence suggests a strong interplay between autophagy and genomic stability. Recently, several papers have demonstrated a molecular connection between the DNA Damage Response (DDR) and autophagy and have explored how this link influences cell fate and the choice between apoptosis and senescence in response to different stimuli. The aberrant deregulation of this interplay is linked to the development of pathologies, including cancer and neurodegeneration. Ataxia-telangiectasia mutated kinase (ATM) is the product of a gene that is lost in Ataxia-Telangiectasia (A-T), a rare genetic disorder characterized by ataxia and cerebellar neurodegeneration, defects in the immune response, higher incidence of lymphoma development, and premature aging. Importantly, ATM kinase plays a central role in the DDR, and it can finely tune the balance between senescence and apoptosis: activated ATM promotes autophagy and in particular sustains the lysosomal-mitochondrial axis, which in turn promotes senescence and inhibits apoptosis. Therefore, ATM is the key factor that enables cells to escape apoptosis by entering senescence through modulation of autophagy. Importantly, unlike apoptotic cells, senescent cells are viable and have the ability to secrete proinflammatory and mitogenic factors, thus influencing the cellular environment. In this review we aim to summarize recent advances in the understanding of molecular mechanisms linking DDR and autophagy to senescence, pointing out the role of ATM kinase in these cellular responses. The significance of this regulation in the pathogenesis of Ataxia-Telangiectasia will be discussed
When S-nitrosylation gets to mitochondria: from signaling to age-related diseases
No full textSignificance: Cysteines have an essential role in redox signaling, transforming an oxidant signal into a biological response. Among reversible cysteine post-translational modifications, S-nitrosylation acts as a redox-switch in several pathophysiological states, such as ischemia/reperfusion, synaptic transmission, cancer, and muscular dysfunctions.
Recent Advances: Growing pieces of in vitro and in vivo evidence argue for S-nitrosylation being deeply involved in development and aging, and playing a role in the onset of different pathological states. New findings suggest it being an enzymatically regulated cellular process, with deep impact on mitochondrial structure and function, and in cellular metabolism. In light of this, the recent discovery of the denitrosylase S-nitrosoCoA (coenzyme A) reductase takes on even greater importance and opens new perspectives on S-nitrosylation as a general mechanism of cellular homeostasis.
Critical Issues: Based on these recent findings, we aim at summarizing and elaborating on the established and emerging crucial roles of S-nitrosylation in mitochondrial metabolism and mitophagy, and provide an overview of the pathophysiological effects induced by its deregulation.
Future Directions: The identification of new S-nitrosylation targets, and the comprehension of the mechanisms through which S-nitrosylation modulates specific classes of proteins, that is, those impinging on diverse mitochondrial functions, may help to better understand the pathophysiology of aging, and propose lines of intervention to slow down or extend the onset of aging-related diseases
SRC Kinase in Glioblastoma: News from an Old Acquaintance
Full text linkGlioblastoma multiforme (GBM) is one of the most recalcitrant brain tumors characterized by a tumor microenvironment (TME) that strongly supports GBM growth, aggressiveness, invasiveness, and resistance to therapy. Importantly, a common feature of GBM is the aberrant activation of receptor tyrosine kinases (RTKs) and of their downstream signaling cascade, including the non-receptor tyrosine kinase SRC. SRC is a central downstream intermediate of many RTKs, which triggers the phosphorylation of many substrates, therefore, promoting the regulation of a wide range of different pathways involved in cell survival, adhesion, proliferation, motility, and angiogenesis. In addition to the aforementioned pathways, SRC constitutive activity promotes and sustains inflammation and metabolic reprogramming concurring with TME development, therefore, actively sustaining tumor growth. Here, we aim to provide an updated picture of the molecular pathways that link SRC to these events in GBM. In addition, SRC targeting strategies are discussed in order to highlight strengths and weaknesses of SRC inhibitors in GBM management, focusing our attention on their potentialities in combination with conventional therapeutic approaches (i.e., temozolomide) to ameliorate therapy effectiveness
Caspase-8: A novel target to overcome resistance to chemotherapy in glioblastoma
Full text linkCaspase-8 was originally identified as a central player of programmed cell death triggered by death receptor stimulation. In that context, its activity is tightly regulated through several mechanisms, with the best established being the expression of FLICE-like inhibitory protein (FLIP) family proteins and the Src-dependent phosphorylation of Caspase-8 on Tyr380. Loss of apoptotic signaling is a hallmark of cancer and indeed Caspase-8 expression is often lost in tumors. This event may account not only for cancer progression but also for cancer resistance to radiotherapy and chemotherapy. Intriguingly, other tumors, such as glioblastoma, preferentially retain Caspase-8 expression, and high levels of Caspase-8 expression may correlate with a worse prognosis, suggesting that in this context this protease loses its apoptotic activity and gains additional functions. Using different cellular systems, it has been clearly shown that in cancer Caspase-8 can exhibit non-canonical functions, including promotion of cell adhesion, migration, and DNA repair. Intriguingly, in glioblastoma models, Caspase-8 can promote NF-κB-dependent expression of several cytokines, angiogenesis, and in vitro and in vivo tumorigenesis. Overall, these observations suggest that some cancer cells may hijack Caspase-8 function which in turn promote cancer progression and resistance to therapy. Here we aim to highlight the multiple functions of Caspase-8 and to discuss whether the molecular mechanisms that modulate the balance between those functions may be targeted to dismantle the aberrant activity of Caspase-8 and to restore its canonical apoptotic functionality
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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