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Article: Strategies to target the cancer driver MYC in tumor cells.

Weber, Leonie I / Hartl, Markus

2023 Volume 13, Page(s) 1142111

Abstract: The MYC oncoprotein functions as a master regulator of cellular transcription and executes non-transcriptional tasks relevant to DNA replication and cell cycle regulation, thereby interacting with multiple proteins. MYC is required for fundamental ... ...

Abstract	The MYC oncoprotein functions as a master regulator of cellular transcription and executes non-transcriptional tasks relevant to DNA replication and cell cycle regulation, thereby interacting with multiple proteins. MYC is required for fundamental cellular processes triggering proliferation, growth, differentiation, or apoptosis and also represents a major cancer driver being aberrantly activated in most human tumors. Due to its non-enzymatic biochemical functions and largely unstructured surface, MYC has remained difficult for specific inhibitor compounds to directly address, and consequently, alternative approaches leading to indirect MYC inhibition have evolved. Nowadays, multiple organic compounds, nucleic acids, or peptides specifically interfering with MYC activities are in preclinical or early-stage clinical studies, but none of them have been approved so far for the pharmacological treatment of cancer patients. In addition, specific and efficient delivery technologies to deliver MYC-inhibiting agents into MYC-dependent tumor cells are just beginning to emerge. In this review, an overview of direct and indirect MYC-inhibiting agents and their modes of MYC inhibition is given. Furthermore, we summarize current possibilities to deliver appropriate drugs into cancer cells containing derailed MYC using viral vectors or appropriate nanoparticles. Finding the right formulation to target MYC-dependent cancers and to achieve a high intracellular concentration of compounds blocking or attenuating oncogenic MYC activities could be as important as the development of novel MYC-inhibiting principles.
Language	English
Publishing date	2023-03-08
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1142111
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Article ; Online: Analysis of Golgi Protein Acetylation Using In Vitro Assays and Parallel Reaction Monitoring Mass Spectrometry.

Slade, Dea / Hartl, Markus

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2557, Page(s) 721–741

Abstract: Acetylation is one of the most abundant post-translational protein modifications that regulates all cellular compartments ranging from chromatin to cytoskeleton and Golgi. The dynamic acetylation of the Golgi stacking protein GRASP55 was shown to ... ...

Abstract	Acetylation is one of the most abundant post-translational protein modifications that regulates all cellular compartments ranging from chromatin to cytoskeleton and Golgi. The dynamic acetylation of the Golgi stacking protein GRASP55 was shown to regulate Golgi reassembly after mitosis. Here we provide a detailed protocol for the analysis of Golgi acetylation including in vitro assays to detect protein acetylation and mass spectrometry analysis to identify specific acetylation sites and their relative abundance.
MeSH term(s)	Golgi Matrix Proteins/metabolism ; Acetylation ; Golgi Apparatus/metabolism ; Protein Processing, Post-Translational ; Mass Spectrometry
Chemical Substances	Golgi Matrix Proteins
Language	English
Publishing date	2022-12-13
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2639-9_43
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Article ; Online: MYC Analysis in Cancer and Evolution.

Hartl, Markus / Bister, Klaus

Methods in molecular biology (Clifton, N.J.)

2021 Volume 2318, Page(s) 87–117

Abstract: The MYC oncogene was originally identified as a transduced allele (v-myc) in the genome of the highly oncogenic avian retrovirus MC29. The protein product (MYC) of the cellular MYC (c-myc) protooncogene represents the key component of a transcription ... ...

Abstract	The MYC oncogene was originally identified as a transduced allele (v-myc) in the genome of the highly oncogenic avian retrovirus MC29. The protein product (MYC) of the cellular MYC (c-myc) protooncogene represents the key component of a transcription factor network controlling the expression of a large fraction of all human genes. MYC regulates fundamental cellular processes like growth control, metabolism, proliferation, differentiation, and apoptosis. Mutational deregulation of MYC, leading to increased levels of the MYC protein, is a frequent event in the etiology of human cancers. In this chapter, we describe cell systems and experimental strategies to quantify the oncogenic potential of MYC alleles, to test MYC inhibitors, and to monitor MYC-specific protein-protein interactions that are relevant for the cell transformation process. We also describe experimental procedures to study the evolutionary origin of MYC and to analyze structure, function, and regulation of the ancestral MYC proto-oncogenes.
MeSH term(s)	Alleles ; Amino Acid Sequence ; Animals ; Carcinogenesis ; Cell Transformation, Neoplastic/genetics ; Evolution, Molecular ; Genes, myc/genetics ; Genes, myc/physiology ; Humans ; Mutation ; Neoplasms/genetics ; Neoplasms/pathology ; Oncogenes ; Protein Interaction Mapping/methods ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Transcription Factors/genetics
Chemical Substances	Proto-Oncogene Proteins c-myc ; Transcription Factors
Language	English
Publishing date	2021-05-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-1476-1_6
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Article: The Quest for Targets Executing MYC-Dependent Cell Transformation.

Hartl, Markus

Frontiers in oncology

2016 Volume 6, Page(s) 132

Abstract: MYC represents a transcription factor with oncogenic potential converting multiple cellular signals into a broad transcriptional response, thereby controlling the expression of numerous protein-coding and non-coding RNAs important for cell proliferation, ...

Abstract	MYC represents a transcription factor with oncogenic potential converting multiple cellular signals into a broad transcriptional response, thereby controlling the expression of numerous protein-coding and non-coding RNAs important for cell proliferation, metabolism, differentiation, and apoptosis. Constitutive activation of MYC leads to neoplastic cell transformation, and deregulated MYC alleles are frequently observed in many human cancer cell types. Multiple approaches have been performed to isolate genes differentially expressed in cells containing aberrantly activated MYC proteins leading to the identification of thousands of putative targets. Functional analyses of genes differentially expressed in MYC-transformed cells had revealed that so far more than 40 upregulated or downregulated MYC targets are actively involved in cell transformation or tumorigenesis. However, further systematic and selective approaches are required for determination of the known or yet unidentified targets responsible for processing the oncogenic MYC program. The search for critical targets in MYC-dependent tumor cells is exacerbated by the fact that during tumor development, cancer cells progressively evolve in a multistep process, thereby acquiring their characteristic features in an additive manner. Functional expression cloning, combinatorial gene expression, and appropriate in vivo tests could represent adequate tools for dissecting the complex scenario of MYC-specified cell transformation. In this context, the central goal is to identify a minimal set of targets that suffices to phenocopy oncogenic MYC. Recently developed genomic editing tools could be employed to confirm the requirement of crucial transformation-associated targets. Knowledge about essential MYC-regulated genes is beneficial to expedite the development of specific inhibitors to interfere with growth and viability of human tumor cells in which MYC is aberrantly activated. Approaches based on the principle of synthetic lethality using MYC-overexpressing cancer cells and chemical or RNAi libraries have been employed to search for novel anticancer drugs, also leading to the identification of several druggable targets. Targeting oncogenic MYC effector genes instead of MYC may lead to compounds with higher specificities and less side effects. This class of drugs could also display a wider pharmaceutical window because physiological functions of MYC, which are important for normal cell growth, proliferation, and differentiation would be less impaired.
Language	English
Publishing date	2016-06-02
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2016.00132
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Article: Lysine acetylome profiling uncovers novel histone deacetylase substrate proteins in Arabidopsis

Hartl, Markus / Sindlinger, Julia / Moorhead, Greg / Schwarzer, Dirk / Mann, Matthias / Finkemeier, Iris

Molecular systems biology, 13(10): 949

2017

Abstract: Histone deacetylases have central functions in regulating stress defenses and development in plants. However, the knowledge about the deacetylase functions is largely limited to histones, although these enzymes were found in diverse subcellular ... ...

Institution	Leibniz-Institut für Molekulare Pharmakologie
Abstract	Histone deacetylases have central functions in regulating stress defenses and development in plants. However, the knowledge about the deacetylase functions is largely limited to histones, although these enzymes were found in diverse subcellular compartments. In this study, we determined the proteome‐wide signatures of the RPD3/HDA1 class of histone deacetylases in Arabidopsis. Relative quantification of the changes in the lysine acetylation levels was determined on a proteome‐wide scale after treatment of Arabidopsis leaves with deacetylase inhibitors apicidin and trichostatin A. We identified 91 new acetylated candidate proteins other than histones, which are potential substrates of the RPD3/HDA1‐like histone deacetylases in Arabidopsis, of which at least 30 of these proteins function in nucleic acid binding. Furthermore, our analysis revealed that histone deacetylase 14 (HDA14) is the first organellar‐localized RPD3/HDA1 class protein found to reside in the chloroplasts and that the majority of its protein targets have functions in photosynthesis. Finally, the analysis of HDA14 loss‐of‐function mutants revealed that the activation state of RuBisCO is controlled by lysine acetylation of RuBisCO activase under low‐light conditions.
Keywords	Arabidopsis ; RuBisCO activase ; histone deacetylases ; lysine acetylation ; photosynthesis
Language	English
Document type	Article
Database	Repository for Life Sciences

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Article ; Online: amica: an interactive and user-friendly web-platform for the analysis of proteomics data.

Didusch, Sebastian / Madern, Moritz / Hartl, Markus / Baccarini, Manuela

BMC genomics

2022 Volume 23, Issue 1, Page(s) 817

Abstract: Background: Quantitative proteomics has become an increasingly prominent tool in the study of life sciences. A substantial hurdle for many biologists are, however, the intricacies involved in the associated high throughput data analysis.: Results: In ...

Abstract	Background: Quantitative proteomics has become an increasingly prominent tool in the study of life sciences. A substantial hurdle for many biologists are, however, the intricacies involved in the associated high throughput data analysis. Results: In order to facilitate this task for users with limited background knowledge, we have developed amica, a freely available open-source web-based software that accepts proteomic input files from different sources. amica provides quality control, differential expression, biological network and over-representation analysis on the basis of minimal user input. Scientists can use amica's query interface interactively to compare multiple conditions and rapidly identify enriched or depleted proteins. They can visualize their results using customized output graphics, and ultimately export the results in a tab-separated format that can be shared with collaborators. The code for the application, input data and documentation can be accessed online at https://github.com/tbaccata/amica and is also incorporated in the web application. Conclusions: The strong emphasis on dynamic user interactions, the integration of various databases and the option to download processed data, facilitate the analysis of complex proteomic data for both first-time users and experienced bioinformaticians. A freely available version of amica is available at https://bioapps.maxperutzlabs.ac.at/app/amica .
Language	English
Publishing date	2022-12-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2041499-7
ISSN	1471-2164 ; 1471-2164
ISSN (online)	1471-2164
ISSN	1471-2164
DOI	10.1186/s12864-022-09058-7
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Article ; Online: Depletion of endogenously biotinylated carboxylases enhances the sensitivity of TurboID-mediated proximity labeling in Caenorhabditis elegans.

Artan, Murat / Hartl, Markus / Chen, Weiqiang / de Bono, Mario

The Journal of biological chemistry

2022 Volume 298, Issue 9, Page(s) 102343

Abstract: Proximity-dependent protein labeling provides a powerful in vivo strategy to characterize the interactomes of specific proteins. We previously optimized a proximity labeling protocol for Caenorhabditis elegans using the highly active biotin ligase ... ...

Abstract	Proximity-dependent protein labeling provides a powerful in vivo strategy to characterize the interactomes of specific proteins. We previously optimized a proximity labeling protocol for Caenorhabditis elegans using the highly active biotin ligase TurboID. A significant constraint on the sensitivity of TurboID is the presence of abundant endogenously biotinylated proteins that take up bandwidth in the mass spectrometer, notably carboxylases that use biotin as a cofactor. In C. elegans, these comprise POD-2/acetyl-CoA carboxylase alpha, PCCA-1/propionyl-CoA carboxylase alpha, PYC-1/pyruvate carboxylase, and MCCC-1/methylcrotonyl-CoA carboxylase alpha. Here, we developed ways to remove these carboxylases prior to streptavidin purification and mass spectrometry by engineering their corresponding genes to add a C-terminal His
MeSH term(s)	Acetyl-CoA Carboxylase/metabolism ; Animals ; Biotinylation/methods ; Caenorhabditis elegans/enzymology ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans Proteins/genetics ; Caenorhabditis elegans Proteins/metabolism ; Carboxy-Lyases/genetics ; Carboxy-Lyases/metabolism ; Carrier Proteins/metabolism ; Intercellular Signaling Peptides and Proteins/metabolism ; Methylmalonyl-CoA Decarboxylase/metabolism ; Pyruvate Carboxylase/metabolism ; Streptavidin
Chemical Substances	Caenorhabditis elegans Proteins ; Carrier Proteins ; Intercellular Signaling Peptides and Proteins ; SYD-2 protein, C elegans ; unc-10 protein, C elegans ; Streptavidin (9013-20-1) ; Carboxy-Lyases (EC 4.1.1.-) ; Pyruvate Carboxylase (EC 6.4.1.1) ; Acetyl-CoA Carboxylase (EC 6.4.1.2) ; Methylmalonyl-CoA Decarboxylase (EC 7.2.4.3)
Language	English
Publishing date	2022-08-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2022.102343
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Article ; Online: Robust synthesis of 2'-azido modified RNA from 2'-amino precursors by diazotransfer reaction.

Moreno, Sarah / Ramos Pittol, José M / Hartl, Markus / Micura, Ronald

Organic & biomolecular chemistry

2022 Volume 20, Issue 39, Page(s) 7845–7850

Abstract: Azides are versatile bioorthogonal reporter moieties that are commonly used for site-specific labeling and functionalization of RNA to probe its biology. The preparation of azido modified nucleic acids by solid-phase synthesis is problematic due to the ... ...

Abstract	Azides are versatile bioorthogonal reporter moieties that are commonly used for site-specific labeling and functionalization of RNA to probe its biology. The preparation of azido modified nucleic acids by solid-phase synthesis is problematic due to the inherent reactivity of P(III) species with azides according to the Staudinger reaction. Various strategies have been developed to bypass this limitation and are often time-consuming, low-yielding and labor-intensive. In particular, the synthesis of RNA with internal 2'-azido modifications is restricted to a single approach that employs P(V) chemistry instead of the widely used P(III) phosphoramidite chemistry. To fill this methodological gap, we present a novel convenient path toward 2'-azido RNA from readily accessible 2'-amino RNA through treatment with the diazotizing reagent fluorosulfuryl azide (FSO
MeSH term(s)	Azides/chemistry ; Oligoribonucleotides ; RNA, Small Interfering ; Thiouridine
Chemical Substances	Azides ; Oligoribonucleotides ; RNA, Small Interfering ; Thiouridine (13957-31-8)
Language	English
Publishing date	2022-10-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2097583-1
ISSN	1477-0539 ; 1477-0520
ISSN (online)	1477-0539
ISSN	1477-0520
DOI	10.1039/d2ob01560a
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Article: A Unique Family of Neuronal Signaling Proteins Implicated in Oncogenesis and Tumor Suppression.

Hartl, Markus / Schneider, Rainer

Frontiers in oncology

2019 Volume 9, Page(s) 289

Abstract: The neuronal proteins GAP43 (neuromodulin), MARCKS, and BASP1 are highly expressed in the growth cones of nerve cells where they are involved in signal transmission and cytoskeleton organization. Although their primary structures are unrelated, these ... ...

Abstract	The neuronal proteins GAP43 (neuromodulin), MARCKS, and BASP1 are highly expressed in the growth cones of nerve cells where they are involved in signal transmission and cytoskeleton organization. Although their primary structures are unrelated, these signaling proteins share several structural properties like fatty acid modification, and the presence of cationic effector domains. GAP43, MARCKS, and BASP1 bind to cell membrane phospholipids, a process reversibly regulated by protein kinase C-phosphorylation or by binding to the calcium sensor calmodulin (CaM). GAP43, MARCKS, and BASP1 are also expressed in non-neuronal cells, where they may have important functions to manage cytoskeleton architecture, and in case of MARCKS and BASP1 to act as cofactors in transcriptional regulation. During neoplastic cell transformation, the proteins reveal differential expression in normal vs. tumor cells, and display intrinsic tumor promoting or tumor suppressive activities. Whereas GAP43 and MARCKS are oncogenic, tumor suppressive functions have been ascribed to BASP1 and in part to MARCKS depending on the cell type. Like MARCKS, the myristoylated BASP1 protein is localized both in the cytoplasm and in the cell nucleus. Nuclear BASP1 participates in gene regulation converting the Wilms tumor transcription factor WT1 from an oncoprotein into a tumor suppressor. The
Language	English
Publishing date	2019-04-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2019.00289
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Article ; Online: A Causal Model of Ion Interference Enables Assessment and Correction of Ratio Compression in Multiplex Proteomics.

Madern, Moritz / Reiter, Wolfgang / Stanek, Florian / Hartl, Natascha / Mechtler, Karl / Hartl, Markus

Molecular & cellular proteomics : MCP

2023 Volume 23, Issue 1, Page(s) 100694

Abstract: Multiplex proteomics using isobaric labeling tags has emerged as a powerful tool for the simultaneous relative quantification of peptides and proteins across multiple experimental conditions. However, the quantitative accuracy of the approach is largely ... ...

Abstract	Multiplex proteomics using isobaric labeling tags has emerged as a powerful tool for the simultaneous relative quantification of peptides and proteins across multiple experimental conditions. However, the quantitative accuracy of the approach is largely compromised by ion interference, a phenomenon that causes fold changes to appear compressed. The degree of compression is generally unknown, and the contributing factors are poorly understood. In this study, we thoroughly characterized ion interference at the MS2 level using a defined two-proteome experimental system with known ground-truth. We discovered remarkably poor agreement between the apparent precursor purity in the isolation window and the actual level of observed reporter ion interference in MS2 scans-a discrepancy that we found resolved by considering cofragmentation of peptide ions hidden within the spectral "noise" of the MS1 isolation window. To address this issue, we developed a regression modeling strategy to accurately predict reporter ion interference in any dataset. Finally, we demonstrate the utility of our procedure for improved fold change estimation and unbiased PTM site-to-protein normalization. All computational tools and code required to apply this method to any MS2 TMT dataset are documented and freely available.
MeSH term(s)	Proteomics/methods ; Peptides ; Proteome/metabolism ; Ions
Chemical Substances	Peptides ; Proteome ; Ions
Language	English
Publishing date	2023-12-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
DOI	10.1016/j.mcpro.2023.100694
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