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6 results on '"Alexander Henrici"'

1. Multi-omics characterization of the monkeypox virus infection

Author

Yiqi Huang, Valter Bergant, Vincent Grass, Quirin Emslander, M. Sabri Hamad, Philipp Hubel, Julia Mergner, Antonio Piras, Karsten Krey, Alexander Henrici, Rupert Öllinger, Yonas M. Tesfamariam, Ilaria Dalla Rosa, Till Bunse, Gerd Sutter, Gregor Ebert, Florian I. Schmidt, Michael Way, Roland Rad, Andrew G. Bowie, Ulrike Protzer, and Andreas Pichlmair

Subjects
Science
Abstract

Abstract Multiple omics analyzes of Vaccinia virus (VACV) infection have defined molecular characteristics of poxvirus biology. However, little is known about the monkeypox (mpox) virus (MPXV) in humans, which has a different disease manifestation despite its high sequence similarity to VACV. Here, we perform an in-depth multi-omics analysis of the transcriptome, proteome, and phosphoproteome signatures of MPXV-infected primary human fibroblasts to gain insights into the virus-host interplay. In addition to expected perturbations of immune-related pathways, we uncover regulation of the HIPPO and TGF-β pathways. We identify dynamic phosphorylation of both host and viral proteins, which suggests that MAPKs are key regulators of differential phosphorylation in MPXV-infected cells. Among the viral proteins, we find dynamic phosphorylation of H5 that influenced the binding of H5 to dsDNA. Our extensive dataset highlights signaling events and hotspots perturbed by MPXV, extending the current knowledge on poxviruses. We use integrated pathway analysis and drug-target prediction approaches to identify potential drug targets that affect virus growth. Functionally, we exemplify the utility of this approach by identifying inhibitors of MTOR, CHUK/IKBKB, and splicing factor kinases with potent antiviral efficacy against MPXV and VACV.

Published
2024
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2. MDM2 Influences ACE2 Stability and SARS-CoV-2 Uptake

Author

Quirin Emslander, Karsten Krey, Sabri Hamad, Susanne Maidl, Lila Oubraham, Joshua Hesse, Alexander Henrici, Katharina Austen, Julia Mergner, Vincent Grass, and Andreas Pichlmair

Subjects
severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), SARS-CoV-2 uptake, MDM2, angiotensin-converting enzyme 2 (ACE2), ubiquitination, Microbiology, QR1-502
Abstract

Angiotensin-converting enzyme 2 (ACE2) is the central entry receptor for SARS-CoV-2. However, surprisingly little is known about the effects of host regulators on ACE2 localization, expression, and the associated influence on SARS-CoV-2 infection. Here we identify that ACE2 expression levels are regulated by the E3 ligase MDM2 and that MDM2 levels indirectly influence infection with SARS-CoV-2. Genetic depletion of MDM2 elevated ACE2 expression levels, which strongly promoted infection with all SARS-CoV-2 isolates tested. SARS-CoV-2 spike-pseudotyped viruses and the uptake of non-replication-competent virus-like particles showed that MDM2 affects the viral uptake process. MDM2 ubiquitinates Lysine 788 of ACE2 to induce proteasomal degradation, and degradation of this residue led to higher ACE2 expression levels and superior virus particle uptake. Our study illustrates that cellular regulators of ACE2 stability, such as MDM2, play an important role in defining the infection capabilities of SARS-CoV-2.

Published
2023
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3. Informationsmanagement und Controlling

Author

Jonas Schreyögg, Gabriele Moos, Frank Brüggemann, Steffen Fleßa, Wolfgang Weber, Stefan Sohn, Katharina Gudd, Hanswerner Voss, Oliver Schöffski, Axel Mühlbacher, Alexander Henrici, Rico Schlösser, Marc-Andrè Pogonke, Maik Büscher, Martin Steigleder, and Manfred G. Krukemeyer

Published
2017

4. The pan-deacetylase inhibitor panobinostat suppresses the expression of oncogenic miRNAs in hepatocellular carcinoma cell lines

Author

Daniel Neureiter, Michael Krause, Karl Quint, Emily P. Slater, Thorsten Stiewe, Matthias Ocker, Pietro Di Fazio, Roberta Montalbano, and Alexander Henrici

Subjects
Cancer Research, Cell growth, Transfection, Biology, chemistry.chemical_compound, Downregulation and upregulation, chemistry, Acetylation, Cell culture, Panobinostat, microRNA, Cancer research, Epigenetics, Molecular Biology
Abstract

Deacetylase inhibitors (DACi) are a new class of drugs with a broad spectrum of mechanisms that favor their application in cancer therapy. Currently, the exact mechanisms and cellular effects of DACi have not been fully elucidated. In addition to their effects on histone acetylation, DACi can interfere with gene expression via miRNA pathways. Treatment with panobinostat (LBH589), a novel potent DACi, led to the highly aberrant modulation of several miRNAs in hepatocellular carcinoma (HCC) cell lines as shown by miRNA array analysis. Among them, hsa-miR-19a, hsa-miR-19b1 and the corresponding precursors were down-regulated by panobinostat in TP53(-/-) Hep3B and TP53(+/+) HepG2 cell lines; hsa-miR30a-5p mature form only was suppressed in both HCC cell lines, as confirmed by further RT-qPCR analysis. In HCC cell lines, panobinostat caused the upregulation of the predicted miRNA targets APAF1 and Beclin1 protein levels. Transfection with oligonucleotides mimicking these miRNAs led to an increase in the viability rate of both cell lines as analyzed by impedance-based real-time cell analysis. In addition, transfecting miRNA mimicking oligonucleotides resulted in the decrease of APAF1, Beclin1 and PAK6 at the protein level, proving the regulating influence of the investigated miRNAs on gene final products. The overexpression of the above mentioned oncomiRs in Hep3B and HepG2 cell lines leads to cell proliferation and downregulation of cell death associated proteins. In our model, panobinostat exerts its anti-cancer effect by suppressing these miRNAs and restoring the expression of their corresponding tumor suppressor targets.

Published
2013

5. The pan-deacetylase inhibitor panobinostat suppresses the expression of oncogenic miRNAs in hepatocellular carcinoma cell lines

Author

Alexander, Henrici, Roberta, Montalbano, Daniel, Neureiter, Michael, Krause, Thorsten, Stiewe, Emily Prentice, Slater, Karl, Quint, Matthias, Ocker, and Pietro, Di Fazio

Subjects
Carcinoma, Hepatocellular, Indoles, Liver Neoplasms, Membrane Proteins, Hep G2 Cells, Hydroxamic Acids, Gene Expression Regulation, Neoplastic, Histone Deacetylase Inhibitors, MicroRNAs, Apoptotic Protease-Activating Factor 1, p21-Activated Kinases, Cell Line, Tumor, Panobinostat, Humans, Beclin-1, Apoptosis Regulatory Proteins, Cell Proliferation
Abstract

Deacetylase inhibitors (DACi) are a new class of drugs with a broad spectrum of mechanisms that favor their application in cancer therapy. Currently, the exact mechanisms and cellular effects of DACi have not been fully elucidated. In addition to their effects on histone acetylation, DACi can interfere with gene expression via miRNA pathways. Treatment with panobinostat (LBH589), a novel potent DACi, led to the highly aberrant modulation of several miRNAs in hepatocellular carcinoma (HCC) cell lines as shown by miRNA array analysis. Among them, hsa-miR-19a, hsa-miR-19b1 and the corresponding precursors were down-regulated by panobinostat in TP53(-/-) Hep3B and TP53(+/+) HepG2 cell lines; hsa-miR30a-5p mature form only was suppressed in both HCC cell lines, as confirmed by further RT-qPCR analysis. In HCC cell lines, panobinostat caused the upregulation of the predicted miRNA targets APAF1 and Beclin1 protein levels. Transfection with oligonucleotides mimicking these miRNAs led to an increase in the viability rate of both cell lines as analyzed by impedance-based real-time cell analysis. In addition, transfecting miRNA mimicking oligonucleotides resulted in the decrease of APAF1, Beclin1 and PAK6 at the protein level, proving the regulating influence of the investigated miRNAs on gene final products. The overexpression of the above mentioned oncomiRs in Hep3B and HepG2 cell lines leads to cell proliferation and downregulation of cell death associated proteins. In our model, panobinostat exerts its anti-cancer effect by suppressing these miRNAs and restoring the expression of their corresponding tumor suppressor targets.

Published
2013

6. Informationsmanagement und Controlling

Author

Jonas Schreyögg, Gabriele Moos, Frank Brüggemann, Steffen Fleßa, Wolfgang Weber, Stefan Sohn, Oliver Schöffski, Hanswerner Voss, Axel C. Mühlbacher, Alexander Henrici, Mechthild König, and Dirk Appel

Abstract

Obwohl der Begriff Controlling sehr weit verbreitet ist, werden die Aufgaben und Ziele des Controllings sehr unterschiedlich interpretiert. Die Bandbreite reicht von der reinen Bereitstellung von Kosten- und Leistungsinformationen bis hin zu einer vollumfassenden Fuhrungsfunktion, die sich uber alle Bereiche einer Organisation erstreckt.

Published
2010

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