1,721,186 research outputs found
Involvement of phospholipase Cgamma1 in mouse egg activation induced by a truncated form of the C-kit tyrosine kinase present in spermatozoa
Full text linkMicroinjection of a truncated form of the c-kit tyrosine kinase present in mouse spermatozoa (tr-kit) activates mouse eggs parthenogenetically, and tr-kit- induced egg activation is inhibited by preincubation with an inhibitor of phospholipase C (PLC) (Sette, C., A. Bevilacqua, A. Bianchini, F. Mangia, R. Geremia, and P. Rossi. 1997. Development [Camb.]. 124:2267-2274). Co-injection of glutathione-S-transferase (GST) fusion proteins containing the src-homology (SH) domains of the gamma1 isoform of PLC (PLCgamma1) competitively inhibits tr-kit- induced egg activation. A GST fusion protein containing the SH3 domain of PLCgamma1 inhibits egg activation as efficiently as the whole SH region, while a GST fusion protein containing the two SH2 domains is much less effective. A GST fusion protein containing the SH3 domain of the Grb2 adaptor protein does not inhibit tr-kit-induced egg activation, showing that the effect of the SH3 domain of PLCgamma1 is specific. Tr-kit-induced egg activation is also suppressed by co-injection of antibodies raised against the PLCgamma1 SH domains, but not against the PLCgamma1 COOH-terminal region. In transfected COS cells, coexpression of PLCgamma1 and tr-kit increases diacylglycerol and inositol phosphate production, and the phosphotyrosine content of PLCgamma1 with respect to cells expressing PLCgamma1 alone. These data indicate that tr-kit activates PLCgamma1, and that the SH3 domain of PLCgamma1 is essential for tr-kit-induced egg activation
Somatic Mutations in Core Spliceosome Components Promote Tumorigenesis and Generate an Exploitable Vulnerability in Human Cancer
Full text linkAlternative pre-mRNA processing enables the production of distinct mRNA and protein isoforms from a single gene, thus greatly expanding the coding potential of eukaryotic genomes and fine-tuning gene expression programs. Splicing is carried out by the spliceosome, a complex molecular machinery which assembles step-wise on mRNA precursors in the nucleus of eukaryotic cells. In the last decade, exome sequencing technologies have allowed the identification of point mutations in genes encoding splicing factors as a recurrent hallmark of human cancers, with higher incidence in hematological malignancies. These mutations lead to production of splicing factors that reduce the fidelity of the splicing process and yield splicing variants that are often advantageous for cancer cells. However, at the same time, these mutations increase the sensitivity of transformed cells to splicing inhibitors, thus offering a therapeutic opportunity for novel targeted strategies. Herein, we review the recent literature documenting cancer-associated mutations in components of the early spliceosome complex and discuss novel therapeutic strategies based on small-molecule spliceosome inhibitors that exhibit strong anti-tumor effects, particularly against cancer cells harboring mutations in spliceosomal components
Rational design of MyD88 inhibitors--new pathways to inflammatory control: an interview with Dr. Claudio Sette by Helene F. Rosenberg.
No full textPost-translational regulation of star proteins and effects on their biological functions
No full textSTAR (Signal Transduction and Activation of RNA) proteins owed their name to the presence in their structure ofa RNA-binding domain and several hallmarks of their involvement in signal transduction pathways. In many members of the family, the STAR RNA-binding domain (also named GSG, an acronym for GRP33/Sam68/ GLD-1) is flanked by regulatory regions containing proline-rich sequences, which serve as docking sites for proteins containing SH3 and WW domains and also a tyrosine-rich region at the C-terminus, which can mediateprotein-protein interactions with partners through SH2 domains. These regulatory regions contain consensus sequences for additional modifications, including serine/threonine phosphorylation, methylation, acetylation and sumoylation. Since their initial description, evidence has been gathered in different cell types and model organisms that STAR proteins can indeed integrate signals from external and internal cues with changes in transcription and processing of target RNAs. The most striking example of the high versatility of STAR proteins is provided by Sam68 (KHDRBS1), whose function, subcellular localization and affinity for RNA are strongly modulated by several signaling pathways through specific modifications. Moreover, the recent development of genetic knockout models has unveiled the physiological function of some STAR proteins, pointing to a crucial role of their post-translational modifications in the biological processes regulated by these RNA-binding proteins. This chapter offers an overview of the most updated literature on the regulation of STAR proteins by post-translational modifications and illustrates examples of how signal transduction pathways can modulate their activity and affect biological processes
Alternative Splicing Programs in Prostate Cancer
Full text linkProstate cancer (PCa) remains one of the most frequent causes of death for cancer in the male population. Although the initial antiandrogenic therapies are efficacious, PCa often evolves into a hormone-resistant, incurable disease. The genetic and phenotypic heterogeneity of this type of cancer renders its diagnosis and cure particularly challenging. Mounting evidence indicates that alternative splicing, the process that allows production of multiple mRNA variants from each gene, contributes to the heterogeneity of the disease. Key genes for the biology of normal and neoplastic prostate cells, such as those encoding for the androgen receptor and cyclin D1, are alternatively spliced to yield protein isoforms with different or even opposing functions. This review illustrates some examples of genes whose alternative splicing regulation is relevant to PCa biology and discusses the possibility to exploit alternative splicing regulation as a novel tool for prognosis, diagnosis, and therapeutic approaches to PCa
Role of RNA-binding proteins in mammalian spermatogenesis
No full textSpermatogenesis is a cell differentiation programme that allows a normally dividing diploid cell to become haploid and to acquire the morphological characteristics required to reach and to fertilize the female gamete. Many of the steps involved in this differentiation programme necessitate profound modifications of the genome, rendering it unable to play its template role for the synthesis of mRNAs. Therefore, de novo transcription is not a continuous process during germ cell differentiation and many mRNAs need to be synthesized and stored at specific times to be available during the transcriptionally inactive stages of spermatogenesis. Germ cells express high levels of RNA-binding proteins that assist these post-transcriptional events. The generation of mouse knockout models has highlighted the essential role played by many of these RNA-binding proteins for the correct progress of spermatogenesis and for the formation of a fertile male gamete. Herein, we review the major findings on the role of RNA-binding proteins in mammalian spermatogenesis
An emerging role for nuclear RNA-mediated responses to genotoxic stress
No full textDefects in the regulation of alternative splicing have strong relevance in the onset and progression of several types of human cancer. Modulation of alternative splicing allows cancer cells to adapt to hostile environments through production of specific mRNA variants. In particular, genotoxic stress exerted by chemotherapeutic drugs or irradiation strongly affects splicing of many genes. A key role in this aberrant regulation is played by the unbalanced expression of several splicing factors in cancer cells. Among them, the RNA-binding protein Sam68, which is overexpressed in various tumors, was shown to accumulate in nuclear foci of active transcription, together with other splicing regulators, and to affect splicing of target mRNAs in response to genotoxic stress. We suggest that subcellular redistribution of splicing factors is guided by changes in chromatin conformation elicited by DNA-damaging drugs. This event might represent an escape mechanism used by cancer cells to survive to genotoxic insults through expression of pro-survival, cancer-specific gene products
Addressing land use planning: A methodology for assessing pre- and post-landslide event urban configurations
Full text linkWith urban areas projected to accommodate 68 % of the global population by 2050, the imperative for inclusive, safe, and sustainable cities becomes paramount. In the timeline of urban centers, landslides represent one of the most destructive phenomena, involving several resources allocation with private and public investments, sometimes claiming human lives. By synergically connecting environmental, planning, and configurational spheres, this study seeks to support the proactive management of landslide risk. The proposed three-step methodology allowed to quantify the environmental features involved in landslide occurrence, evaluate planning framework vulnerabilities, and suggest alternative configurations for urban areas that experienced landslides. The methodology has been applied to the case study involving a tragic landslide in Casamicciola Terme (Italy) in November 2022. First, the stream network and the drainage basin corresponding to confluence point of the landslide into the sea have been calculated (environmental elaborations). Subsequently, these elaborations have been overlapped with the runoff mitigation and the sediment deposition layers, extracted through the INVEST software. Secondly, the reconnaissance of the local and superordinate planning levels has been realized, to deepen planning tools cogency on the study area, contextually deepening the constraints that characterize it. From the overlapping of these two steps, free landslide risk areas have been located. Finally, based on the available territorial surface (Sta) and the territorial cover ratio (Rct), two territorial configuration scenarios have been proposed, envisaging the relocation of the buildings involved into the landslide. Results show that landslide originated by three out of five gullies. Some portions of the urban areas of Casamicciola Terme are still under high and very high hydrogeological risk. Contextually, it emerges poor attention from the local planners to the superordinate planning framework. Historic settlement has an Rct of 33.64 %, while areas in which relocate the built up show an Rct of 32,45 % for scenario 1 and 27,9 % for scenario 2. The methodology resulted useful to address planning vulnerabilities, supporting the realization of alternative configurational scenarios. We expect our research to contribute to the evolving field of disaster risk reduction, by providing a systematic approach to manage landslide risk
Modulation of cellular responses by hormones: role of cAMP specific, rolipram-sensitive phosphodiesterase
No full textL'emergenza nell'emergenza: il progetto C.A.S.E. di Sassa NSI
No full textThe L’Aquila earthquake of 2009 activated an emergency response that took shape in the
building of new temporary residential areas. Among these sites, there is one of the 19 C.A.S.E.
projects located in the northwest periphery of L’Aquila, in the hamlet of Sassa. The area is
bordered on one side by important regional infrastructure and on the other by the river Raio. In
December 2010, during the post-earthquake emergency, this residential complex was flooded
by the previously mentioned river. Many proposals were made aimed at giving new life to this
complex, but none of them includes measures to mitigate the hydrogeological risk that has
occurred several times (2010, 2019). Considering this, these kinds of actions are essential to
ensure safe use. This work wants to show some possible useful solutions to the highlighted
problem through the targeted use of Nature-Based Solutions (NBSs), whose choice is conveyed
by the analysis of some in-force planning tools
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