Dataset Information

Characterization of p38 MAPK isoforms for drug resistance study using systems biology approach.

ABSTRACT:

Motivation

p38 mitogen-activated protein kinase activation plays an important role in resistance to chemotherapeutic cytotoxic drugs in treating multiple myeloma (MM). However, how the p38 mitogen-activated protein kinase signaling pathway is involved in drug resistance, in particular the roles that the various p38 isoforms play, remains largely unknown.

Method

To explore the underlying mechanisms, we developed a novel systems biology approach by integrating liquid chromatography-mass spectrometry and reverse phase protein array data from human MM cell lines with computational pathway models in which the unknown parameters were inferred using a proposed novel algorithm called modularized factor graph.

Results

New mechanisms predicted by our models suggest that combined activation of various p38 isoforms may result in drug resistance in MM via regulating the related pathways including extracellular signal-regulated kinase (ERK) pathway and NF?B pathway. ERK pathway regulating cell growth is synergistically regulated by p38? isoform, whereas nuclear factor kappa B (NF?B) pathway regulating cell apoptosis is synergistically regulated by p38? isoform. This finding that p38? isoform promotes the phosphorylation of ERK1/2 in MM cells treated with bortezomib was validated by western blotting. Based on the predicted mechanisms, we further screened drug combinations in silico and found that a promising drug combination targeting ERK1/2 and NF?B might reduce the effects of drug resistance in MM cells. This study provides a framework of a systems biology approach to studying drug resistance and drug combination selection.

Availability and implementation

RPPA experimental Data and Matlab source codes of modularized factor graph for parameter estimation are freely available online at http://ctsb.is.wfubmc.edu/publications/modularized-factor-graph.php.

SUBMITTER: Peng H

PROVIDER: S-EPMC4071201 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Publications

Characterization of p38 MAPK isoforms for drug resistance study using systems biology approach.

Peng Huiming H Peng Tao T Wen Jianguo J Engler David A DA Matsunami Risë K RK Su Jing J Zhang Le L Chang Chung-Che Jeff CC Zhou Xiaobo X

Bioinformatics (Oxford, England) 20140310 13

<h4>Motivation</h4>p38 mitogen-activated protein kinase activation plays an important role in resistance to chemotherapeutic cytotoxic drugs in treating multiple myeloma (MM). However, how the p38 mitogen-activated protein kinase signaling pathway is involved in drug resistance, in particular the roles that the various p38 isoforms play, remains largely unknown.<h4>Method</h4>To explore the underlying mechanisms, we developed a novel systems biology approach by integrating liquid chromatography- ...[more]

PMID: 24618474

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Project description:BackgroundRhodopseudomonas palustris (R. palustris) is a purple non-sulfur anoxygenic phototrophic bacterium that belongs to the class of proteobacteria. It is capable of absorbing atmospheric carbon dioxide and converting it to biomass via the process of photosynthesis and the Calvin-Benson-Bassham (CBB) cycle. Transketolase is a key enzyme involved in the CBB cycle. Here, we reveal the functions of transketolase isoforms I and II in R. palustris using a systems biology approach.Methodology/principal findingsBy measuring growth ability, we found that transketolase could enhance the autotrophic growth and biomass production of R. palustris. Microarray and real-time quantitative PCR revealed that transketolase isoforms I and II were involved in different carbon metabolic pathways. In addition, immunogold staining demonstrated that the two transketolase isoforms had different spatial localizations: transketolase I was primarily associated with the intracytoplasmic membrane (ICM) but transketolase II was mostly distributed in the cytoplasm. Comparative proteomic analysis and network construction of transketolase over-expression and negative control (NC) strains revealed that protein folding, transcriptional regulation, amino acid transport and CBB cycle-associated carbon metabolism were enriched in the transketolase I over-expressed strain. In contrast, ATP synthesis, carbohydrate transport, glycolysis-associated carbon metabolism and CBB cycle-associated carbon metabolism were enriched in the transketolase II over-expressed strain. Furthermore, ATP synthesis assays showed a significant increase in ATP synthesis in the transketolase II over-expressed strain. A PEPCK activity assay showed that PEPCK activity was higher in transketolase over-expressed strains than in the negative control strain.Conclusions/significanceTaken together, our results indicate that the two isoforms of transketolase in R. palustris could affect photoautotrophic growth through both common and divergent metabolic mechanisms.

Dataset Information

Characterization of p38 MAPK isoforms for drug resistance study using systems biology approach.

Motivation

Method

Results

Availability and implementation

Publications

Characterization of p38 MAPK isoforms for drug resistance study using systems biology approach.

Similar Datasets

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