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      Proteomic variations of esophageal squamous cell carcinoma revealed by combining RNA-seq proteogenomics and G-PTM search strategy

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          Abstract

          Background

          Cancer that arises from epithelial cells of the esophagus is called esophagus squamous cell carcinoma (ESCC) and is mostly observed in developing nations. Evaluation of cancer genomes and its regulation into proteins plays a predominant role in understanding the cancer progressions. Mass-spectrometry-based proteomics is a consequential tool to estimate proteomic variation and posttranslational modifications (PTMs) from standard protein databases. Post-translational modifications play a crucial role in protein folding and PTMs can be accounted for as a biological signal to interpret the structural changes and transition order of proteins. Functional validation of cancer-related mutations can explain the effects of mutations on genes and the identification of Oncogenes and tumor suppressor genes. Therefore, we present a study on protein variations to interpret the structural changes and transition order of proteins in ESCC carcinogenesis.

          Methodology

          We are using a bottom-up proteomics approach with Galaxy-P framework and RNA sequence data analysis to generate the sample-specific databases containing details of RNA splicing and variant peptides. Once the database generated with information on variable modification, only the curated PTMs at specific positions are considered to perform spectral matching. Proteogenomics mapping was performed to identify protein variations in ESCC.

          Results

          RNA-sequence proteogenomics with G-PTM (Global Post-Translational Modification) searching strategy has revealed proteomic events including several peptides that contain single amino acid variations, novel splice junction peptides and posttranslationally modified peptides. Proteogenomic mapping exhibited the splice junction peptides mapped predominantly for Malic enzyme exon type (ME-3) and MCM7 protein-coding genes that promote cancer progression, found to be exhibited in ESCC samples. Approximately 25 ± types of PTM modifications were recorded, and Protein Phosphorylation was largely noted.

          Conclusion

          ESCC cancer prognosis at the molecular level enables a better understanding of cancer carcinogenesis and protein modifications can be used as potential biomarkers.

          Abstract

          Bioinformatics, Cancer Research, Genetics, Oncology, Proteogenomics, Esophageal squamous cell carcinoma, PTM, RNA-seq proteogenomics, bottom-up proteomics

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          Most cited references32

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          Large-scale analysis of the yeast proteome by multidimensional protein identification technology.

          We describe a largely unbiased method for rapid and large-scale proteome analysis by multidimensional liquid chromatography, tandem mass spectrometry, and database searching by the SEQUEST algorithm, named multidimensional protein identification technology (MudPIT). MudPIT was applied to the proteome of the Saccharomyces cerevisiae strain BJ5460 grown to mid-log phase and yielded the largest proteome analysis to date. A total of 1,484 proteins were detected and identified. Categorization of these hits demonstrated the ability of this technology to detect and identify proteins rarely seen in proteome analysis, including low-abundance proteins like transcription factors and protein kinases. Furthermore, we identified 131 proteins with three or more predicted transmembrane domains, which allowed us to map the soluble domains of many of the integral membrane proteins. MudPIT is useful for proteome analysis and may be specifically applied to integral membrane proteins to obtain detailed biochemical information on this unwieldy class of proteins.
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            The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review)

            Protein phosphorylation is an important cellular regulatory mechanism as many enzymes and receptors are activated/deactivated by phosphorylation and dephosphorylation events, by means of kinases and phosphatases. In particular, the protein kinases are responsible for cellular transduction signaling and their hyperactivity, malfunction or overexpression can be found in several diseases, mostly tumors. Therefore, it is evident that the use of kinase inhibitors can be valuable for the treatment of cancer. In this review, we discuss the mechanism of action of phosphorylation, with particular attention to the importance of phosphorylation under physiological and pathological conditions. We also discuss the possibility of using kinase inhibitors in the treatment of tumors.
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              Small Changes Huge Impact: The Role of Protein Posttranslational Modifications in Cellular Homeostasis and Disease

              Posttranslational modifications (PTMs) modulate protein function in most eukaryotes and have a ubiquitous role in diverse range of cellular functions. Identification, characterization, and mapping of these modifications to specific amino acid residues on proteins are critical towards understanding their functional significance in a biological context. The interpretation of proteome data obtained from the high-throughput methods cannot be deciphered unambiguously without a priori knowledge of protein modifications. An in-depth understanding of protein PTMs is important not only for gaining a perception of a wide array of cellular functions but also towards developing drug therapies for many life-threatening diseases like cancer and neurodegenerative disorders. Many of the protein modifications like ubiquitination play a decisive role in various drug response(s) and eventually in disease prognosis. Thus, many commonly observed PTMs are routinely tracked as disease markers while many others are used as molecular targets for developing target-specific therapies. In this paper, we summarize some of the major, well-studied protein alterations and highlight their importance in various chronic diseases and normal development. In addition, other promising minor modifications such as SUMOylation, observed to impact cellular dynamics as well as disease pathology, are mentioned briefly.
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                Author and article information

                Contributors
                Journal
                Heliyon
                Heliyon
                Heliyon
                Elsevier
                2405-8440
                29 August 2020
                August 2020
                29 August 2020
                : 6
                : 8
                : e04813
                Affiliations
                [1]Department of Biotechnology, RV College of Engineering, Bangalore, Karnataka, India
                Author notes
                []Corresponding author. vidya.n@ 123456rvce.edu.in
                Article
                S2405-8440(20)31656-X e04813
                10.1016/j.heliyon.2020.e04813
                7472856
                2b4c4aef-43ca-46f0-99a4-e15effb102c3
                © 2020 The Authors. Published by Elsevier Ltd.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 24 May 2020
                : 10 July 2020
                : 25 August 2020
                Categories
                Article

                bioinformatics,cancer research,genetics,oncology,proteogenomics,esophageal squamous cell carcinoma,ptm,rna-seq proteogenomics,bottom-up proteomics

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