Network Modeling and Control of Dynamic Disease Pathways, Review and Perspectives DOI
Yen-Che Hsiao, Abhishek Dutta

IEEE/ACM Transactions on Computational Biology and Bioinformatics, Journal Year: 2024, Volume and Issue: 21(5), P. 1211 - 1230

Published: March 18, 2024

Dynamic disease pathways are a combination of complex dynamical processes among bio-molecules in cell that leads to diseases. Network modeling considers disease-related (e.g. DNA, RNA, transcription factors, enzymes, proteins, and metabolites) their interaction DNA methylation, histone modification, alternative splicing, protein modification) study progression predict therapeutic responses. These interactions the basic elements misregulation gene expression lead abnormal cellular Gene regulatory networks, signaling metabolic networks three major types intracellular for responses elicited from extracellular signals. The can be prevented or regulated by designing control strategies manipulate these other paper reviews mechanisms, dynamic models, each network. applications, limitations prospective also discussed.

Language: Английский

Dynamic regulation of RAS and RAS signaling DOI Creative Commons
Walter Kölch, Dénes Berta, Edina Rosta

et al.

Biochemical Journal, Journal Year: 2023, Volume and Issue: 480(1), P. 1 - 23

Published: Jan. 6, 2023

RAS proteins regulate most aspects of cellular physiology. They are mutated in 30% human cancers and 4% developmental disorders termed Rasopathies. cycle between active GTP-bound inactive GDP-bound states. When active, they can interact with a wide range effectors that control fundamental biochemical biological processes. Emerging evidence suggests not simple on/off switches but sophisticated information processing devices compute cell fate decisions by integrating external internal cues. A critical component this function is the dynamic regulation activation downstream signaling allows to produce rich nuanced spectrum outputs. We discuss recent findings how dynamics its regulated. Starting from structural properties wild-type mutant their cycle, we examine higher molecular assemblies, effector interactions outputs, all under aspect regulation. also consider computational mathematical modeling approaches contribute analyze understand pleiotropic functions health disease.

Language: Английский

Citations

57
Spatiotemporal control of ERK pulse frequency coordinates fate decisions during mammary acinar morphogenesis DOI Creative Commons
Pascal Ender, Paolo Armando Gagliardi, Maciej Dobrzyński

et al.

Developmental Cell, Journal Year: 2022, Volume and Issue: 57(18), P. 2153 - 2167.e6

Published: Sept. 1, 2022

Language: Английский

Citations

54
Optogenetic activators of apoptosis, necroptosis, and pyroptosis DOI Creative Commons
Kateryna Shkarina, Eva Hasel, José Carlos Santos

et al.

The Journal of Cell Biology, Journal Year: 2022, Volume and Issue: 221(6)

Published: April 14, 2022

Targeted and specific induction of cell death in an individual or groups cells hold the potential for new insights into response tissues organisms to different forms death. Here, we report development optogenetically controlled effectors (optoCDEs), a novel class optogenetic tools that enables light-mediated three types programmed (PCD)—apoptosis, pyroptosis, necroptosis—using Arabidopsis thaliana photosensitive protein Cryptochrome-2. OptoCDEs enable rapid highly PCD human, mouse, zebrafish are suitable wide range applications, such as sub-lethal precise elimination single populations vitro vivo. As proof-of-concept, utilize optoCDEs assess differences neighboring responses apoptotic necrotic PCD, revealing role shingosine-1-phosphate signaling regulating efferocytosis by epithelia.

Language: Английский

Citations

51
Optogenetic actuator – ERK biosensor circuits identify MAPK network nodes that shape ERK dynamics DOI
Coralie Dessauges, Jan Mikelson, Maciej Dobrzyński

et al.

Molecular Systems Biology, Journal Year: 2022, Volume and Issue: 18(6)

Published: June 1, 2022

Language: Английский

Citations

44
Deep model predictive control of gene expression in thousands of single cells DOI Creative Commons
Jean‐Baptiste Lugagne, Caroline M. Blassick, Mary J. Dunlop

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 8, 2024

Abstract Gene expression is inherently dynamic, due to complex regulation and stochastic biochemical events. However, the effects of these dynamics on cell phenotypes can be difficult determine. Researchers have historically been limited passive observations natural dynamics, which preclude studies elusive noisy cellular events where large amounts data are required reveal statistically significant effects. Here, using recent advances in fields machine learning control theory, we train a deep neural network accurately predict response an optogenetic system Escherichia coli cells. We then use model predictive framework impose arbitrary cell-specific gene thousands single cells real time, applying generate time-varying patterns. also showcase framework’s ability link patterns dynamic functional outcomes by controlling tetA antibiotic resistance gene. This study highlights how learning-enabled feedback used tailor distributions with high accuracy throughput without expert knowledge biological system.

Language: Английский

Citations

13
Targeting Extracellular Signal-Regulated Protein Kinase 1/2 (ERK1/2) in Cancer: An Update on Pharmacological Small-Molecule Inhibitors DOI
Leilei Fu, Siwei Chen, Gu He

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 65(20), P. 13561 - 13573

Published: Oct. 7, 2022

Extracellular signal-regulated protein kinase 1/2 (ERK1/2), the only known substrate of MEK1/2, is located downstream RAS-RAF-MEK-ERK (MAPK) pathway and associated with abnormal activation poor prognosis cancer. To date, several small-molecule inhibitors RAS, RAF, MEK have been reported to make rapid advances in cancer therapy; however, acquired resistance still occurs, thereby weakening therapeutic efficacy these inhibitors. Recently, selective inhibition ERK1/2 has regarded as a potential strategy that can not effectively block MAPK but also overcome drug caused by upstream mutations MEK. Herein, we summarize oncogenic roles, key signaling network, single- dual-target preclinical clinical trials. Together, inspiring findings shed new light on discovery more candidate drugs improve therapeutics.

Language: Английский

Citations

35
Kinetics of RTK activation determine ERK reactivation and resistance to dual BRAF/MEK inhibition in melanoma DOI Creative Commons
Sung Soo Kim, Richard D. Carvajal, Minah Kim

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(6), P. 112570 - 112570

Published: May 29, 2023

The combination of BRAF and MEK inhibitors (BRAFi/MEKi) has shown promising response rates in treating BRAF-mutant melanoma by inhibiting ERK activation. However, treatment efficacy is limited the emergence drug-tolerant persister cells (persisters). Here, we show that magnitude duration receptor tyrosine kinase (RTK) activation determine reactivation development. Our single-cell analysis reveals only a small subset exhibits effective RTK develops persisters, despite uniform external stimuli. kinetics directly influence signaling dynamics These initially rare persisters form major resistant clones through RTK-mediated Consequently, limiting suppresses cell proliferation drug-resistant cells. findings provide non-genetic mechanistic insights into role heterogeneity BRAFi/MEKi resistance, suggesting potential strategies for overcoming drug resistance melanoma.

Language: Английский

Citations

19
An improved Erk biosensor detects oscillatory Erk dynamics driven by mitotic erasure during early development DOI Creative Commons
Scott G. Wilcockson, Luca Guglielmi,

Pablo Araguas Rodriguez

et al.

Developmental Cell, Journal Year: 2023, Volume and Issue: 58(23), P. 2802 - 2818.e5

Published: Sept. 15, 2023

Extracellular signal-regulated kinase (Erk) signaling dynamics elicit distinct cellular responses in a variety of contexts. The early zebrafish embryo is an ideal model to explore the role Erk vivo, as gradient activated diphosphorylated (P-Erk) induced by fibroblast growth factor (Fgf) at blastula margin. Here, we describe improved Erk-specific biosensor, which term modified translocation reporter (modErk-KTR). We demonstrate utility this biosensor vitro and developing Drosophila embryos. Moreover, show that Fgf/Erk dynamic coupled tissue during both development. activity rapidly extinguished just prior mitosis, refer mitotic erasure, inducing periods inactivity, thus providing source heterogeneity asynchronously dividing tissue. Our transgenic lines represent important resource for interrogating vivo.

Language: Английский

Citations

18
Rapid Optogenetic Clustering in the Cytoplasm with BcLOVclust DOI Creative Commons
Zikang Huang, William Benman, Liang Dong

et al.

Journal of Molecular Biology, Journal Year: 2024, Volume and Issue: 436(3), P. 168452 - 168452

Published: Jan. 21, 2024

Language: Английский

Citations

9
Oncogenic Kras induces spatiotemporally specific tissue deformation through converting pulsatile into sustained ERK activation DOI
Tianchi Xin, Sara Gallini, Haoyang Wei

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(6), P. 859 - 867

Published: April 30, 2024

Language: Английский

Citations

8