Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(3), P. 1102 - 1102

Published: Feb. 7, 2020

Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous signal transduction that regulate all aspects of life and are frequently altered in disease. Here, we focus on the role MAPK modulating drug sensitivity resistance cancer. We briefly discuss new findings extracellular signaling-regulated (ERK) pathway, but mainly mechanisms how stress activated pathways, such as p38 Jun N-terminal kinases (JNK), impact response cancer cells to chemotherapies targeted therapies. In this context, also metabolic epigenetic aberrations therapeutic opportunities arising from these changes.

Language: Английский

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TNF and MAP kinase signalling pathways

Seminars in Immunology, Journal Year: 2014, Volume and Issue: 26(3), P. 237 - 245

Published: March 20, 2014

Language: Английский

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Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP)

Cellular Signalling, Journal Year: 2011, Volume and Issue: 24(4), P. 835 - 845

Published: Dec. 12, 2011

The major hallmark of cellular senescence is an irreversible cell cycle arrest and thus it a potent tumor suppressor mechanism. Genotoxic insults, e.g. oxidative stress, are important inducers the senescent phenotype which characterized by accumulation senescence-associated heterochromatic foci (SAHF) DNA segments with chromatin alterations reinforcing (DNA-SCARS). Interestingly, cells secrete pro-inflammatory factors condition has been called secretory (SASP). Emerging data revealed that NF-κB signaling pathway stimulates appearance SASP. It known damage provokes via variety complexes containing NEMO protein, essential modifier, as well activation pathways p38MAPK RIG-1, retinoic acid inducible gene-1. Genomic instability evoked stress triggers epigenetic changes, release HMGB1 proteins also enhancers inflammatory responses. Moreover, environmental chronic inflammation can stimulate ceramide induce On other hand, two cyclin-dependent kinase inhibitors, p16INK4a p14ARF, effective inhibitors signaling. We will review in detail activate trigger SASP cells.

Language: Английский

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Tau protein kinases: Involvement in Alzheimer's disease

Ageing Research Reviews, Journal Year: 2012, Volume and Issue: 12(1), P. 289 - 309

Published: June 26, 2012

Language: Английский

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Biomarkers, oxidative stress and autophagy in skin aging

Ageing Research Reviews, Journal Year: 2020, Volume and Issue: 59, P. 101036 - 101036

Published: Feb. 24, 2020

Language: Английский

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PROTACs: great opportunities for academia and industry

Signal Transduction and Targeted Therapy, Journal Year: 2019, Volume and Issue: 4(1)

Published: Dec. 24, 2019

Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic limited number drug targets, which presently only 20-25% all protein targets that currently being studied. Moreover, focus current explorations their enzymatic functions, ignores functions from scaffold moiety. As promising appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both academia industry for finding available approaches to solve above problems. PROTACs regulate function by degrading target proteins instead inhibiting them, providing more sensitivity drug-resistant greater chance affect nonenzymatic functions. been proven show better selectivity compared classic inhibitors. can be described as chemical knockdown approach with rapidity reversibility, presents new different biology other gene editing tools avoiding misinterpretations arise potential genetic compensation and/or spontaneous mutations. PRTOACs widely explored throughout world outperformed not cancer diseases, but also immune disorders, viral infections neurodegenerative diseases. present very powerful crossing hurdles discovery tool development biology, efforts needed gain get deeper insight into efficacy safety clinic. More binders E3 ligases applicable developing waiting exploration.

Language: Английский

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Role of p38 MAP Kinase Signal Transduction in Solid Tumors

Genes & Cancer, Journal Year: 2013, Volume and Issue: 4(9-10), P. 342 - 359

Published: Sept. 1, 2013

Mitogen-activated protein kinases (MAPKs) mediate a wide variety of cellular behaviors in response to extracellular stimuli. One the main subgroups, p38 MAP kinases, has been implicated range complex biologic processes, such as cell proliferation, differentiation, death, migration, and invasion. Dysregulation MAPK levels patients are associated with advanced stages short survival cancer (e.g., prostate, breast, bladder, liver, lung cancer). plays dual role regulator it can either or death depending not only on type stimulus but also specific manner. In addition modulating survival, an essential modulation migration invasion offers distinct opportunity target this pathway respect tumor metastasis. The function appears depend stimuli and/or isoform that is activated. signaling activated diverse mediates its by components downstream p38. Extrapolation knowledge gained from laboratory findings address clinical significance pathways. goal review provide overview recent progress made defining functions pathways solid biology generate testable hypothesis attractive for intervention tumors.

Language: Английский

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Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Jan. 4, 2019

Abstract PROteolysis-TArgeting Chimeras (PROTACs) are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted degradation. Many potent PROTACs with specificity for dissimilar targets have been developed; however, the factors governing degradation selectivity within closely-related families remain elusive. Here, we generate isoform-selective p38 MAPK family using single warhead (foretinib) and recruited (von Hippel-Lindau). Based on their distinct linker attachments lengths, these two differentially VHL, of p38α or p38δ. We characterize role ternary complex formation driving selectivity, showing it is necessary, but insufficient, PROTAC-induced ubiquitination. Lastly, explore p38δ:PROTAC:VHL explain different profiles PROTACs. Our work attributes selective proteins same heretofore underappreciated aspects model.

Language: Английский

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Diversity and versatility of p38 kinase signalling in health and disease

Nature Reviews Molecular Cell Biology, Journal Year: 2021, Volume and Issue: 22(5), P. 346 - 366

Published: Jan. 27, 2021

Language: Английский

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Cell Signaling and Stress Responses

Cold Spring Harbor Perspectives in Biology, Journal Year: 2016, Volume and Issue: 8(10), P. a006072 - a006072

Published: Oct. 1, 2016

Stress-signaling pathways are evolutionarily conserved and play an important role in the maintenance of homeostasis. These also critical for adaptation to new cellular environments. The endoplasmic reticulum (ER) unfolded protein response (UPR) is activated by biosynthetic stress leads a compensatory increase ER function. JNK p38 MAPK signaling control adaptive responses intracellular extracellular stresses, including environmental changes such as UV light, heat, hyperosmotic conditions, exposure inflammatory cytokines. Metabolic caused high-fat diet represents example stimulus that coordinately activates both UPR JNK/p38 pathways. Chronic activation these stress-response ultimately causes metabolic associated with obesity altered insulin sensitivity. pathways, therefore, represent potential targets therapeutic intervention other disease processes.

Language: Английский

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