14 research outputs found
Role of SOX family of transcription factors in central nervous system tumors
SOX genes are developmental regulators with functions in the instruction of cell fate and maintenance of
progenitorâs identity during embryogenesis. They play additional roles during tissue homeostasis and regeneration
in adults particularly in the Central Nervous System (CNS). In the last years a growing number of evidences has
shown that mutations and dysfunction of SOX factors are implicated in several human diseases, including a variety
of cancers. In this review, we will summarize the current knowledge about SOX family in CNS tumors and their role
in the origin and maintenance of the subpopulation of cancer stem cells in these tumors
Neuronal p38α mediates synaptic and cognitive dysfunction in an Alzheimerâs mouse model by controlling ÎČ-amyloid production.
Alzheimerâs disease (AD) is a neurodegenerative disorder characterized by a severe and progressive neuronal loss leading to cognitive dysfunctions. Previous reports, based on the use of chemical inhibitors, have connected the stress kinase p38α to neuroinflammation, neuronal death and synaptic dysfunction. To explore the specific role of neuronal p38α signalling in the appearance of pathological symptoms, we have generated mice that combine expression of the 5XFAD transgenes to induce AD symptoms with the downregulation of p38α only in neurons (5XFAD/p38αâ-N). We found that the neuronal-specific deletion of p38α improves the memory loss and long-term potentiation impairment induced by 5XFAD transgenes. Furthermore, 5XFAD/p38αâ-N mice display reduced amyloid-ÎČ accumulation, improved neurogenesis, and important changes in brain cytokine expression compared with 5XFAD mice. Our results implicate neuronal p38α signalling in the synaptic plasticity dysfunction and memory impairment observed in 5XFAD mice, by regulating both amyloid-ÎČ deposition in the brain and the relay of this accumulation to mount an inflammatory response, which leads to the cognitive deficits.post-print1848 K
Neuronal p38α mediates ageâassociated neural stem cell exhaustion and cognitive decline
[EN] Neuronal activity regulates cognition and neural stem cell (NSC) function. The molecular pathways limiting neuronal activity during aging remain largely unknown. In this work, we show that p38MAPK activity increases in neurons with age. By using mice expressing p38α-lox and CamkII-Cre alleles (p38αâ-N), we demonstrate that genetic deletion of p38α in neurons suffices to reduce age-associated elevation of p38MAPK activity, neuronal loss and cognitive decline. Moreover, aged p38αâ-N mice present elevated numbers of NSCs in the hippocampus and the subventricular zone. These results reveal novel roles for neuronal p38MAPK in age-associated NSC exhaustion and cognitive decline
Role of SOX family of transcription factors in central nervous system tumors
SOX genes are developmental regulators with functions in the instruction of cell fate and maintenance of
progenitorâs identity during embryogenesis. They play additional roles during tissue homeostasis and regeneration
in adults particularly in the Central Nervous System (CNS). In the last years a growing number of evidences has
shown that mutations and dysfunction of SOX factors are implicated in several human diseases, including a variety
of cancers. In this review, we will summarize the current knowledge about SOX family in CNS tumors and their role
in the origin and maintenance of the subpopulation of cancer stem cells in these tumors
Antiviral action of the tumor suppressor ARF
Oncogenic viruses frequently target the pathways controlled by tumor suppressor genes, suggesting an extra function for these proteins as antiviral factors. The control exerted by the tumor suppressor Arf on cellular proliferation is crucial to restrict tumor development; however, a potential contribution of Arf to prevent viral infectivity has remained unexplored. In the present study, we investigated the consequences of loss or increased expression of Arf on viral infection. Our results reveal that ARF expression is induced by interferon and after viral infection. Furthermore, we show that ARF protects against viral infection in a gene dosageâdependent manner, and that this antiviral action is mediated in part by PKR through a mechanism that involves ARFâinduced release of PKR from nucleophosmin complexes. Finally, Arfânull mice were hypersensitive to viral infection compared to wildâtype mice. Together, our results reveal a novel and unexpected role for the tumor suppressor ARF in viral infection surveillance.ME is funded by the Spanish Ministry of Education and Science (BIO2002â03246) and by the European Union (QLK2â2002â01687 and QLK2âCTâ2002â00954). Work at the laboratory of MS has been funded by the Spanish Ministry of Education and Science (SAF2002â03402) and by the European Union (INTACT and PROTEOMAGE). CR is funded by the Spanish Ministry of Education and Science (BIO2005â00599) and the Fundacion Medica Mutua Madrileña
High levels of HDAC expression correlate with microglial aging
Background: Cellular damage gradually accumulates with aging, promoting a time-dependent functional decline of the brain. Microglia play an essential regulatory role in maintaining cognitive activity by phagocytosing cell debris and apoptotic cells during neurogenesis. The activities of different histone deacetylases (HDACs) regulate microglial function during development and neurodegeneration. However, no studies have described the role of HDACs in microglia during physiological aging. Research design and methods: HDAC and microglial marker levels were examined in microglial cells after inducing senescence in vitro and in mouse and human hippocampal biopsies in vivo, using quantitative real-time PCR. Publicly available datasets were used to determine HDAC expression in different brain areas during physiological aging. Results: HDAC expression increased upon the induction of senescence with bleomycin or serial passage in microglial cultures. High levels of HDACs were detected in mice and aged human brain samples. Human hippocampal samples showed a positive correlation between the expression of HDAC1, 3, and 7 and microglial and senescence markers. HDAC1 and 3 levels are enriched in the purified aged microglial population. Conclusions: Several HDACs, particularly HDAC1, are elevated in microglia upon senescence induction in vitro and with aging invivo, and correlate with microglial and senescence biomarkers.J Auzmendi-Iriarte (PRE_2016_1_0375), L Moreno-Cugnon (PRE_2014_1_92) and A Saenz- Antoñanzas (FI17/00250) received predoctoral fellowships from Department of Education, University and Research of the Basque Government and Carlos III Institute, respectively. J Auzmendi-Iriarte received an EMBO Scientific Exchange Grant (number 8775) for developing experiments in the group of IC Wood in the University of Leeds. This work is supported by grants from Instituto de Salud Carlos III co-financed by European Union (PI19/01355, DTS20/00179) and Health Department of the Basque Country
Antiviral action of the tumor suppressor ARF
Oncogenic viruses frequently target the pathways controlled by tumor suppressor genes, suggesting an extra function for these proteins as antiviral factors. The control exerted by the tumor suppressor Arf on cellular proliferation is crucial to restrict tumor development; however, a potential contribution of Arf to prevent viral infectivity has remained unexplored. In the present study, we investigated the consequences of loss or increased expression of Arf on viral infection. Our results reveal that ARF expression is induced by interferon and after viral infection. Furthermore, we show that ARF protects against viral infection in a gene dosage-dependent manner, and that this antiviral action is mediated in part by PKR through a mechanism that involves ARF-induced release of PKR from nucleophosmin complexes. Finally, Arf-null mice were hypersensitive to viral infection compared to wild-type mice. Together, our results reveal a novel and unexpected role for the tumor suppressor ARF in viral infection surveillance
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Designing a broad-spectrum integrative approach for cancer prevention and treatment.
Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered