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Ines Tomašković

Bio: Ines Tomašković is an academic researcher from Goethe University Frankfurt. The author has contributed to research in topics: Cancer & Ubiquitin. The author has an hindex of 1, co-authored 2 publications receiving 1 citations.

Papers
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Journal ArticleDOI
04 Oct 2021-Cells
TL;DR: In this article, the authors discuss the emerging role of USP28 in cancer and discuss the complexity and mutational landscape of squamous tumors, as well as the genetic alterations and cellular pathways that determine the function of USp28 in squamous cancer.
Abstract: Squamous cell carcinomas are therapeutically challenging tumor entities. Low response rates to radiotherapy and chemotherapy are commonly observed in squamous patients and, accordingly, the mortality rate is relatively high compared to other tumor entities. Recently, targeting USP28 has been emerged as a potential alternative to improve the therapeutic response and clinical outcomes of squamous patients. USP28 is a catalytically active deubiquitinase that governs a plethora of biological processes, including cellular proliferation, DNA damage repair, apoptosis and oncogenesis. In squamous cell carcinoma, USP28 is strongly expressed and stabilizes the essential squamous transcription factor ΔNp63, together with important oncogenic factors, such as NOTCH1, c-MYC and c-JUN. It is presumed that USP28 is an oncoprotein; however, recent data suggest that the deubiquitinase also has an antineoplastic effect regulating important tumor suppressor proteins, such as p53 and CHK2. In this review, we discuss: (1) The emerging role of USP28 in cancer. (2) The complexity and mutational landscape of squamous tumors. (3) The genetic alterations and cellular pathways that determine the function of USP28 in squamous cancer. (4) The development and current state of novel USP28 inhibitors.

12 citations

Journal ArticleDOI
TL;DR: It is shown that synthetic UbADPr analogues can be used to effectively pull‐down overexpressed DupA from cell lysate and the inhibitory effects of modified Ub on the canonical eukaryotic E1‐enzyme Uba1 are investigated and rationalized.
Abstract: Legionnaires' disease is caused by infection with the intracellularly replicating Gram-negative bacterium Legionella pneumophila. This pathogen uses an unconventional way of ubiquitinating host proteins by generating a phosphoribosyl linkage between substrate proteins and ubiquitin by making use of an ADPribosylated ubiquitin (UbADPr ) intermediate. The family of SidE effector enzymes that catalyze this reaction is counteracted by Legionella hydrolases, which are called Dups. This unusual ubiquitination process is important for Legionella proliferation and understanding these processes on a molecular level might prove invaluable in finding new treatments. Herein, a modular approach is used for the synthesis of triazole-linked UbADPr , and analogues thereof, and their affinity towards the hydrolase DupA is determined and hydrolysis rates are compared to natively linked UbADPr . The inhibitory effects of modified Ub on the canonical eukaryotic E1-enzyme Uba1 are investigated and rationalized in the context of a high-resolution crystal structure reported herein. Finally, it is shown that synthetic UbADPr analogues can be used to effectively pull-down overexpressed DupA from cell lysate.

6 citations


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Journal ArticleDOI
TL;DR: Recently, the ubiquitin system has become synonymous with the modification of lysine residues as mentioned in this paper , but the substrate scope and diversity of the conjugation machinery have been underappreciated.
Abstract: The ubiquitin system has become synonymous with the modification of lysine residues. However, the substrate scope and diversity of the conjugation machinery have been underappreciated, bringing us to an epoch in ubiquitin system research. The striking discoveries of metazoan enzymes dedicated toward serine and threonine ubiquitination have revealed the important role of nonlysine ubiquitination in endoplasmic reticulum–associated degradation, immune signaling and neuronal processes, while reports of nonproteinaceous substrates have extended ubiquitination beyond the proteome. Bacterial effectors that bypass the canonical ubiquitination machinery and form unprecedented linkage chemistry further redefine long-standing dogma. While chemical biology approaches have advanced our understanding of the canonical ubiquitin system, further study of noncanonical ubiquitination has been hampered by a lack of suitable tools. This Perspective aims to consolidate and contextualize recent discoveries and to propose potential applications of chemical biology, which will be instrumental in unraveling this new frontier of ubiquitin research. Emerging evidence shows that ubiquitination can occur on nonlysine residues and nonproteinaceous substrates. This perspective summarizes the recent discoveries in noncanonical ubiquitination and advocates the development of chemical biology tools for new substrate identification and mechanistic dissection.

16 citations

Journal ArticleDOI
TL;DR: In this article , the authors summarize the current understanding of Legionella pneumophila from medical, biochemical and molecular perspectives, with the emphasis on the ability of the Legionella to target the host ubiquitin system upon infection.

6 citations

Journal ArticleDOI
TL;DR: In this article , the progress in the chemical protein synthesis of state-of-the-art Ub and Ub-like chemical probes, their unique concepts and related discoveries in the ubiquitin field are discussed.

6 citations

Journal ArticleDOI
23 Sep 2022-Cancers
TL;DR: Research progress on the MAPK signaling pathway and its potential therapeutic mechanisms are reviewed and its molecular targeting technologies combined with immune checkpoint therapies to provide new therapeutic strategies for oral squamous cell carcinoma are discussed.
Abstract: Simple Summary The aim of the present review was to summarize our studies on the signaling pathways in cancer types that are involved in the development of oral cancer and several mitogen-activated protein kinase-related molecular targeting technologies combined with immune checkpoint therapies to provide new therapeutic strategies for oral squamous cell carcinoma. In addition, we have provided a reasonable outlook, with a systematic basis, for future diagnosis and accurate treatment. Abstract Oral squamous cell carcinoma accounts for 95% of human head and neck squamous cell carcinoma cases. It is highly malignant and aggressive, with a poor prognosis and a 5-year survival rate of <50%. In recent years, basic and clinical studies have been performed on the role of the mitogen-activated protein kinase (MAPK) signaling pathway in oral cancer. The MAPK signaling pathway is activated in over 50% of human oral cancer cases. Herein, we review research progress on the MAPK signaling pathway and its potential therapeutic mechanisms and discuss its molecular targeting to explore its potential as a therapeutic strategy for oral squamous cell carcinoma.

5 citations

Journal ArticleDOI
TL;DR: In this article , the arginine residue was modified with an adenosine-di-phosphate-ribosyl (ADPr) group to obtain four regioisomers of the same type of protein.
Abstract: We describe the development and optimization of a methodology to prepare peptides and proteins modified on the arginine residue with an adenosine-di-phosphate-ribosyl (ADPr) group. Our method comprises reacting an ornithine containing polypeptide on-resin with an α-linked anomeric isothiourea N-riboside, ensuing installment of a phosphomonoester at the 5′-hydroxyl of the ribosyl moiety followed by the conversion into the adenosine diphosphate. We use this method to obtain four regioisomers of ADP-ribosylated ubiquitin (UbADPr), each modified with an ADP-ribosyl residue on a different arginine position within the ubiquitin (Ub) protein (Arg42, Arg54, Arg72, and Arg74) as the first reported examples of fully synthetic arginine-linked ADPr-modified proteins. We show the chemically prepared Arg-linked UbADPr to be accepted and processed by Legionella enzymes and compare the entire suite of four Arg-linked UbADPr regioisomers in a variety of biochemical experiments, allowing us to profile the activity and selectivity of Legionella pneumophila ligase and hydrolase enzymes.

4 citations