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Your search keyword '"Levandowski, Cecilia B."' showing total 11 results
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11 results on '"Levandowski, Cecilia B."'

1. Mediator kinase inhibition impedes transcriptional plasticity and prevents resistance to ERK/MAPK-targeted therapy in KRAS-mutant cancers

Author

Nussbaum, Daniel P., Martz, Colin A., Waters, Andrew M., Barrera, Alejandro, Liu, Annie, Rutter, Justine C., Cerda-Smith, Christian G., Stewart, Amy E., Wu, Chao, Cakir, Merve, Levandowski, Cecilia B., Kantrowitz, David E., McCall, Shannon J., Pierobon, Mariaelena, Petricoin, III, Emanuel F., Joshua Smith, J., Reddy, Timothy E., Der, Channing J., Taatjes, Dylan J., and Wood, Kris C.

Published
2024
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2. Suppression of p53 response by targeting p53-Mediator binding with a stapled peptide

Author

Allen, Benjamin L, Quach, Kim, Jones, Taylor, Levandowski, Cecilia B, Ebmeier, Christopher C, Rubin, Jonathan D, Read, Timothy, Dowell, Robin D, Schepartz, Alanna, and Taatjes, Dylan J

Subjects
Biochemistry and Cell Biology, Biological Sciences, Human Genome, Biotechnology, Genetics, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Generic health relevance, Humans, Molecular Probes, Peptides, Protein Binding, Transcription Factors, Tumor Suppressor Protein p53, AP-MS, CP: Molecular biology, ChIP-seq, Mediator complex, Nutlin-3a, RNA-seq, chemical biology, in vitro transcription, molecular probes, p53, proteomics, stapled peptide, transcription, Medical Physiology, Biological sciences
Abstract

DNA-binding transcription factors (TFs) remain challenging to target with molecular probes. Many TFs function in part through interaction with Mediator, a 26-subunit complex that controls RNA polymerase II activity genome-wide. We sought to block p53 function by disrupting the p53-Mediator interaction. Through rational design and activity-based screening, we characterize a stapled peptide, with functional mimics of both p53 activation domains, that blocks p53-Mediator binding and selectively inhibits p53-dependent transcription in human cells; importantly, this "bivalent" peptide has negligible impact, genome-wide, on non-p53 target genes. Our proof-of-concept strategy circumvents the TF entirely and targets the TF-Mediator interface instead, with desired functional outcomes (i.e., selective inhibition of p53 activation). Furthermore, these results demonstrate that TF activation domains represent viable starting points for Mediator-targeting molecular probes, as an alternative to large compound libraries. Different TFs bind Mediator through different subunits, suggesting this strategy could be broadly applied to selectively alter gene expression programs.

Published
2022

4. Transcriptional Responses to IFN-γ Require Mediator Kinase-Dependent Pause Release and Mechanistically Distinct CDK8 and CDK19 Functions

Author

Steinparzer, Iris, Sedlyarov, Vitaly, Rubin, Jonathan D., Eislmayr, Kevin, Galbraith, Matthew D., Levandowski, Cecilia B., Vcelkova, Terezia, Sneezum, Lucy, Wascher, Florian, Amman, Fabian, Kleinova, Renata, Bender, Heather, Andrysik, Zdenek, Espinosa, Joaquin M., Superti-Furga, Giulio, Dowell, Robin D., Taatjes, Dylan J., and Kovarik, Pavel

Published
2019
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5. Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to ERK/MAPK-Targeted Therapy in KRAS-Mutant Cancers

Author

Nussbaum, Daniel P., primary, Martz, Colin A., additional, Waters, Andrew M., additional, Barrera, Alejandro, additional, Rutter, Justine C., additional, Cerda-Smith, Christian G., additional, Stewart, Amy E., additional, Wu, Chao, additional, Cakir, Merve, additional, Levandowski, Cecilia B., additional, Kantrowitz, David E., additional, McCall, Shannon J, additional, Pierobon, Mariaelena, additional, Petricoin, Emanuel F., additional, Smith, J. Joshua, additional, Reddy, Timothy E., additional, Der, Channing J., additional, Taatjes, Dylan J., additional, and Wood, Kris C., additional

Published
2022
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7. Abstract 3509: Immune modulation in immune co-cultures of pancreatic ductal adenocarcinoma by small molecule CLK/WNT pathway inhibitor SM04690

Author

Dominguez, Adrian TA, primary, Real, Adreanna G., additional, Levandowski, Cecilia B., additional, Lewis, Matthew S., additional, Hartman, Sarah, additional, Yacob, Betelehem, additional, Smoots, Stephen, additional, Schreiber, Anna, additional, Lanis, Jordi, additional, Nepal, Pragya, additional, Diamond, Jennifer, additional, Lieu, Chris, additional, Messersmith, Wells, additional, Lang, Julie, additional, and Pitts, Todd, additional

Published
2022
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10. Transcriptional responses to IFN-γ require Mediator kinase-dependent pause release and mechanistically distinct functions of CDK8 and CDK19

Author

Steinparzer, Iris, Sedlyarov, Vitaly, Rubin, Jonathan D., Eislmayr, Kevin, Galbraith, Matthew D., Levandowski, Cecilia B., Vcelkova, Terezia, Sneezum, Lucy, Wascher, Florian, Amman, Fabian, Kleinova, Renata, Bender, Heather, Andrysik, Zdenek, Espinosa, Joaquin M., Superti-Furga, Giulio, Dowell, Robin D., Taatjes, Dylan J., and Kovarik, Pavel

Subjects
Mice, Knockout, Transcription, Genetic, Vesiculovirus, Fibroblasts, Cyclin-Dependent Kinase 8, HCT116 Cells, Article, Cyclin-Dependent Kinases, Mice, Inbred C57BL, Interferon-gamma, Mice, STAT1 Transcription Factor, Host-Pathogen Interactions, Animals, Humans, RNA Polymerase II, Phosphorylation, Signal Transduction
Abstract

Transcriptional responses to external stimuli remain poorly understood. Using global nuclear run-on followed by sequencing (GRO-seq) and precision nuclear run-on sequencing (PRO-seq), we show that CDK8 kinase activity promotes RNA polymerase II pause release in response to interferon-γ (IFN-γ), a universal cytokine involved in immunity and tumor surveillance. The Mediator kinase module contains CDK8 or CDK19, which are presumed to be functionally redundant. We implemented cortistatin A, chemical genetics, transcriptomics, and other methods to decouple their function while assessing enzymatic versus structural roles. Unexpectedly, CDK8 and CDK19 regulated different gene sets via distinct mechanisms. CDK8-dependent regulation required its kinase activity, whereas CDK19 governed IFN-γ responses through its scaffolding function (i.e., it was kinase independent). Accordingly, CDK8, not CDK19, phosphorylates the STAT1 transcription factor (TF) during IFN-γ stimulation, and CDK8 kinase inhibition blocked activation of JAK-STAT pathway TFs. Cytokines such as IFN-γ rapidly mobilize TFs to "reprogram" cellular transcription; our results implicate CDK8 and CDK19 as essential for this transcriptional reprogramming.

Published
2019

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