Long non-coding RNAs: A view to kill ovarian cancer Zamaraev, Alexey V.; Volik, Pavel I.; Sukhikh, Gennady T. ...
Biochimica et biophysica acta. Reviews on cancer,
08/2021, Volume:
1876, Issue:
1
Journal Article
Peer reviewed
Open access
An emerging role of long non-coding RNAs (lncRNAs) in tumor progression has been revealed in the last decade. Through interactions with nucleic acids and proteins, lncRNAs could act as enhancers, ...scaffolds or decoys for a number of oncoproteins and tumor suppressors. The aberrant lncRNA expression or mutations are often associated with changes in a variety of cellular processes, including proliferation, stress response and cell death. Here, we will focus on the tumor-associated lncRNAs in ovarian cancer according to their contribution to cancer hallmarks, such as intense proliferation, cell death resistance, altered energy metabolism, invasion and metastasis, and immune evasion. Moreover, the potential clinical implications of lncRNAs and their significance for the diagnosis, prognosis and therapy of ovarian cancer will be discussed.
•Ovarian cancer (OC) is a widespread type of cancer among women, which is difficult to diagnose due to the almost asymptomatic course at the early stages.•Deregulated expression or mutations of lncRNAs are associated with cancer hallmarks.•The vigorous studies of lncRNA led to development of the new strategies of OC diagnosis and prognosis based on the intracellular and exosomal lncRNA levels.•Post-transcriptional regulation of lncRNAs by antisense oligonucleotides or CRISPR/Cas9 genomic editing break new ground in modulation of cellular signaling pathways to overcome the chemotherapy resistance and prevent OC progression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Caspase-2 activity modulates AMP receptor trafficking and dendritic spine dynamics.A soluble tau fragment generated by caspase-2 is elevated in Alzheimer’s disease, Huntington's disease, and Lewy ...body disease and promotes cognitive defects.The genetic ablation of caspase-2 leads to symptomatic benefits in transgenic mice overexpressing mutant huntingtin or the amyloid-β precursor protein.Biallelic mutations in genes encoding p53-induced protein with a death domain 1, receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain cause intellectual, behavioral, and psychological abnormalities of varying severity, predominantly accompanied by pachygyria.Selective PIDDosome component inhibitors protect against neurotoxicity in in vitro models, which makes them promising therapeutic agents for the treatment of neurodegenerative diseases.
The PIDDosome is a multiprotein complex that includes p53-induced protein with a death domain 1 (PIDD1), receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD), and caspase-2, the activation of which is driven by PIDDosome assembly. In addition to the key role of the PIDDosome in the regulation of cell differentiation, tissue homeostasis, and organogenesis and regeneration, caspase-2, RAIDD and PIDD1 engagement in neuronal development was shown. Here, we focus on the involvement of PIDDosome components in neurodegenerative disorders, including retinal neuropathies, different types of brain damage, and Alzheimer’s disease (AD), Huntington’s disease (HD), and Lewy body disease. We also discuss pathogenic variants of PIDD1, RAIDD, and caspase-2 that are associated with intellectual, behavioral, and psychological abnormalities, together with prospective PIDDosome inhibition strategies and their potential clinical application.
The PIDDosome is a multiprotein complex that includes p53-induced protein with a death domain 1 (PIDD1), receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD), and caspase-2, the activation of which is driven by PIDDosome assembly. In addition to the key role of the PIDDosome in the regulation of cell differentiation, tissue homeostasis, and organogenesis and regeneration, caspase-2, RAIDD and PIDD1 engagement in neuronal development was shown. Here, we focus on the involvement of PIDDosome components in neurodegenerative disorders, including retinal neuropathies, different types of brain damage, and Alzheimer’s disease (AD), Huntington’s disease (HD), and Lewy body disease. We also discuss pathogenic variants of PIDD1, RAIDD, and caspase-2 that are associated with intellectual, behavioral, and psychological abnormalities, together with prospective PIDDosome inhibition strategies and their potential clinical application.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ
Caspase-2 is a unique and conservative cysteine protease which plays an important role in several cellular processes including apoptotic cell death. Although the molecular mechanisms of its ...activation remain largely unclear, a major role belongs to the architecture of the caspase-2 active center. We demonstrate that the substitution of the putative phosphorylation site of caspase-2, Serine-384 to Alanine, blocks caspase-2 processing and decreases its enzymatic activity. Strikingly, in silico analysis using molecular dynamics simulations has shown that Serine-384 is crucially involved in interactions within the caspase-2 active center. It stabilizes Arginine-378, which forms a crucial hydrogen bond with the aspartate residue of a substrate. Hence, Serine-384 is essential for supporting a proper architecture of the active center of caspase-2. Moreover, molecular modeling strongly proved steric inaccessibility of Ser-384 to be phosphorylated. Importantly, a multiple alignment has demonstrated that both Serine-384 and Arg-378 residues are highly conservative across all members of caspase family, which allows us to suggest that this diade is indispensable for caspase processing and activity. Spontaneous mutations in this diade might influence oncosuppressive function of caspases, in particular of caspase-2. Likewise, the mutation of Ser-384 is associated with the development of lung squamous cell carcinoma and adenocarcinoma. Taken together, we have uncovered a central feature of the caspase-2 activation mechanism which is crucial for the regulation of its signaling network.
Reconstructing tumor genome architectures Raphael, Benjamin J.; Volik, Stanislav; Collins, Colin ...
Bioinformatics,
09/2003, Volume:
19, Issue:
suppl-2
Journal Article
Peer reviewed
Open access
Although cancer progression is often associated with genome rearrangements, little is known about the detailed genomic architecture of tumor genomes. The attempt to reconstruct the genomic ...organization of a tumor genome recently resulted in the development of the End Sequence Profiling (ESP) technique, and the application of this technique to human MCF7 tumor cells. We formulate the ESP Genome Reconstruction Problem, and develop an algorithm to solve this problem in the case of sparse ESP data. We apply our algorithm to analyze human MCF7 tumor cells, and obtain the first reconstruction of the putative architecture of human MCF7 tumor genome. Our results assist in the ongoing ESP analysis of MCF7 tumors by suggesting additional ESP experiments for the completion of a reliable reconstruction of the MCF7 tumor genome, and by focusing BAC re-sequencing efforts. Contact: braphael@ucsd.edu * To whom correspondence should be addressed.
A comprehensive understanding of cancer is predicated upon knowledge of the structure of malignant genomes underlying its many variant forms and the molecular mechanisms giving rise to them. It is ...well established that solid tumor genomes accumulate a large number of genome rearrangements during tumorigenesis. End Sequence Profiling (ESP) maps and clones genome breakpoints associated with all types of genome rearrangements elucidating the structural organization of tumor genomes. Here we extend the ESP methodology in several directions using the breast cancer cell line MCF-7. First, targeted ESP is applied to multiple amplified loci, revealing a complex process of rearrangement and co-amplification in these regions reminiscent of breakage/fusion/bridge cycles. Second, genome breakpoints identified by ESP are confirmed using a combination of DNA sequencing and PCR. Third, in vitro functional studies assign biological function to a rearranged tumor BAC clone, demonstrating that it encodes anti-apoptotic activity. Finally, ESP is extended to the transcriptome identifying four novel fusion transcripts and providing evidence that expression of fusion genes may be common in tumors. These results demonstrate the distinct advantages of ESP including: (1) the ability to detect all types of rearrangements and copy number changes; (2) straightforward integration of ESP data with the annotated genome sequence; (3) immortalization of the genome; (4) ability to generate tumor-specific reagents for in vitro and in vivo functional studies. Given these properties, ESP could play an important role in a tumor genome project.
It has been shown that in order to obtain oxide coatings with desired properties, in the process of their synthesis, it is necessary to measure and control the technological parameters and properties ...of the coatings. The authors proposed an automated system for the synthesis and study of coating parameters by the micro-arc oxidation method. An algorithm for the selection of methods and instruments for measuring technological modes and parameters of synthesized coatings according to technical and economic indicators and a method for choosing the optimal means for measuring technological parameters of the microarc oxidation process according to technical and economic indicators based on the average gain criterion have been developed. The analyzed technical indicators include metrological characteristics of measuring instruments. The technique was implemented in the selection of optimal measuring instruments for coating parameters in the process of micro-arc oxidation, which confirmed the relevance of the development of an automated system for the synthesis of coatings with specified properties, with a relative measurement error of the parameters not exceeding ±0.5 % by micro-arc oxidation.
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