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578 results on '"Kholodenko, Boris N."'

2. Control of cell state transitions

Author

Rukhlenko, Oleksii S., Halasz, Melinda, Rauch, Nora, Zhernovkov, Vadim, Prince, Thomas, Wynne, Kieran, Maher, Stephanie, Kashdan, Eugene, MacLeod, Kenneth, Carragher, Neil O., Kolch, Walter, and Kholodenko, Boris N.

Published
2022
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3. Cell State Transition Models Stratify Breast Cancer Cell Phenotypes and Reveal New Therapeutic Targets.

Author

Rukhlenko, Oleksii S., Imoto, Hiroaki, Tambde, Ayush, McGillycuddy, Amy, Junk, Philipp, Tuliakova, Anna, Kolch, Walter, and Kholodenko, Boris N.

Subjects
BREAST tumor treatment, FLOW cytometry, PHOSPHORYLATION, RESEARCH funding, BREAST tumors, CANCER cell culture, CELL motility, CELL lines, GENETIC mutation, PHENOTYPES, SIGNAL peptides
Abstract

Simple Summary: We utilized publicly available perturbation phosphoproteomic data to construct models elucidating cell state transitions across multiple breast cancer and normal breast tissue-derived cell lines. Employing a hybrid methodology, which integrates machine learning and mechanistic modeling, we separated luminal, basal, and normal cell states and revealed core networks that control cell state transitions. We determined causal connections within the core networks and developed interpretable mechanistic models that elucidated the drivers of cell phenotypes. Significantly, these models can predict synergistic drug combinations capable of potentially reversing oncogenic transformation in breast cancer cell lines. Our methodology will enable designer approaches to identify targeted perturbations that convert cell states and mechanistically underpin therapeutic interventions. Understanding signaling patterns of transformation and controlling cell phenotypes is a challenge of current biology. Here we applied a cell State Transition Assessment and Regulation (cSTAR) approach to a perturbation dataset of single cell phosphoproteomic patterns of multiple breast cancer (BC) and normal breast tissue-derived cell lines. Following a separation of luminal, basal, and normal cell states, we identified signaling nodes within core control networks, delineated causal connections, and determined the primary drivers underlying oncogenic transformation and transitions across distinct BC subtypes. Whereas cell lines within the same BC subtype have different mutational and expression profiles, the architecture of the core network was similar for all luminal BC cells, and mTOR was a main oncogenic driver. In contrast, core networks of basal BC were heterogeneous and segregated into roughly four major subclasses with distinct oncogenic and BC subtype drivers. Likewise, normal breast tissue cells were separated into two different subclasses. Based on the data and quantified network topologies, we derived mechanistic cSTAR models that serve as digital cell twins and allow the deliberate control of cell movements within a Waddington landscape across different cell states. These cSTAR models suggested strategies of normalizing phosphorylation networks of BC cell lines using small molecule inhibitors. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Control of Spatially Heterogeneous and Time-Varying Cellular Reaction Networks: A New Summation Law

Author

Peletier, Mark A., Westerhoff, Hans V., and Kholodenko, Boris N.

Subjects
Mathematics - Analysis of PDEs, Quantitative Biology, 35B30 (Primary) 35J60, 35K55 (Secondary)
Abstract

A hallmark of a plethora of intracellular signaling pathways is the spatial separation of activation and deactivation processes that potentially results in precipitous gradients of activated proteins. The classical Metabolic Control Analysis (MCA), which quantifies the influence of an individual process on a system variable as the control coefficient, cannot be applied to spatially separated protein networks. The present paper unravels the principles that govern the control over the fluxes and intermediate concentrations in spatially heterogeneous reaction networks. Our main results are two types of the control summation theorems. The first type is a non-trivial generalization of the classical theorems to systems with spatially and temporally varying concentrations. In this generalization, the process of diffusion, which enters as the result of spatial concentration gradients, plays a role similar to other processes such as chemical reactions and membrane transport. The second summation theorem is completely novel. It states that the control by the membrane transport, the diffusion control coefficient multiplied by two, and a newly introduced control coefficient associated with changes in the spatial size of a system (e.g., cell), all add up to one and zero for the control over flux and concentration. Using a simple example of a kinase/phosphatase system in a spherical cell, we speculate that unless active mechanisms of intracellular transport are involved, the threshold cell size is limited by the diffusion control, when it is beginning to exceed the spatial control coefficient significantly., Comment: 19 pages, AMS-LaTeX, 6 eps figures included with geompsfi.sty

Published
2002

12. Determination of Functional Network Structure from Local Parameter Dependence Data

Author

Kholodenko, Boris N. and Sontag, Eduardo D.

Subjects
Physics - Biological Physics, Mathematics - Dynamical Systems, Mathematics - Optimization and Control, Quantitative Biology
Abstract

In many applications, such as those arising from the field of cellular networks, it is often desired to determine the interaction (graph) structure of a set of differential equations, using as data measured sensitivities. This note proposes an approach to this problem.

Published
2002

15. Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D

Author

Kennedy, Susan A., Jarboui, Mohamed-Ali, Srihari, Sriganesh, Raso, Cinzia, Bryan, Kenneth, Dernayka, Layal, Charitou, Theodosia, Bernal-Llinares, Manuel, Herrera-Montavez, Carlos, Krstic, Aleksandar, Matallanas, David, Kotlyar, Max, Jurisica, Igor, Curak, Jasna, Wong, Victoria, Stagljar, Igor, LeBihan, Thierry, Imrie, Lisa, Pillai, Priyanka, Lynn, Miriam A., Fasterius, Erik, Al-Khalili Szigyarto, Cristina, Breen, James, Kiel, Christina, Serrano, Luis, Rauch, Nora, Rukhlenko, Oleksii, Kholodenko, Boris N., Iglesias-Martinez, Luis F., Ryan, Colm J., Pilkington, Ruth, Cammareri, Patrizia, Sansom, Owen, Shave, Steven, Auer, Manfred, Horn, Nicola, Klose, Franziska, Ueffing, Marius, Boldt, Karsten, Lynn, David J., and Kolch, Walter

Published
2020
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20. Bimodal Protein Distributions in Heterogeneous Oscillating Systems

Author

Dobrzyński, Maciej, Fey, Dirk, Nguyen, Lan K., Kholodenko, Boris N., Hutchison, David, Series editor, Kanade, Takeo, Series editor, Kittler, Josef, Series editor, Kleinberg, Jon M., Series editor, Mattern, Friedemann, Series editor, Mitchell, John C., Series editor, Naor, Moni, Series editor, Nierstrasz, Oscar, Series editor, Pandu Rangan, C., Series editor, Steffen, Bernhard, Series editor, Sudan, Madhu, Series editor, Terzopoulos, Demetri, Series editor, Tygar, Doug, Series editor, Vardi, Moshe Y., Series editor, Weikum, Gerhard, Series editor, Istrail, Sorin, Series editor, Pevzner, Pavel, Series editor, Waterman, Michael S., Series editor, Gilbert, David, editor, and Heiner, Monika, editor

Published
2012
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30. Modeling cell line-specific recruitment of signaling proteins to the insulin-like growth factor 1 receptor

Author

Erickson, Keesha E., primary, Rukhlenko, Oleksii S., additional, Shahinuzzaman, Md., additional, Slavkova, Kalina P., additional, Lin, Yen Ting, additional, Stites, Edward C., additional, Anghel, Marian, additional, Posner, Richard G., additional, Barua, Dipak, additional, Kholodenko, Boris N., additional, and Hlavacek, William S., additional

Published
2018
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34. Multiplicity of Control

Author

Westerhoff, Hans V., Jensen, Peter Ruhdal, van der Gugten, Anton A., Kahn, Daniel, Kholodenko, Boris N., Schuster, Stefan, Oldenburg, Nienke, van Dam, Karel, van Heeswijk, Wally C., Schuster, Stefan, editor, Rigoulet, Michel, editor, Ouhabi, Rachid, editor, and Mazat, Jean-Pierre, editor

Published
1993
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44. Maladaptive oxidative stress cascade drives type I interferon hyperactivity in TNF activated macrophages promoting necrosis in murine tuberculosis granulomas

Author

Brownhill, Eric, primary, Yabaji, Shivraj M., additional, Zhernovkov, Vadim, additional, Rukhlenko, Oleksii S., additional, Seidel, Kerstin, additional, Bhattacharya, Bidisha, additional, Chatterjee, Sujoy, additional, Chen, Hui A., additional, Crossland, Nicholas, additional, Bishai, William, additional, Kholodenko, Boris N., additional, Gimelbrant, Alexander, additional, Kobzik, Lester, additional, and Kramnik, Igor, additional

Published
2020
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50. Temperature dependence of the epidermal growth factor receptor signaling network can be accounted for by a kinetic model

Author

Moehren, Gisela, Markevich, Nick, Demin, Oleg, Kiyatkin, Anatoly, Goryanin, Igor, Hoek, Jan B., and Kholodenko, Boris N.

Subjects
Biochemistry -- Research, Temperature -- Physiological aspects, Epidermal growth factor -- Physiological aspects, Proteins -- Receptors, Phosphorylation -- Physiological aspects, Tyrosine -- Physiological aspects, Biological sciences, Chemistry
Abstract

Research has been conducted on the isolated hepatocytes simulated with the epidermal growth factor (EGF) which cause tyrosine phosphorylation of the EGF receptor and adapter proteins. The mechanistic kinetic model of the EGF receptor pathway, the cascades of the protein interactions and phosphorylation and dephosphorylation reactions, has been developed and the details are presented.

Published
2002

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