Nuclear ERK: Mechanism of Translocation, Substrates, and Role in Cancer

International Journal of Molecular Sciences, Год журнала: 2019, Номер 20(5), С. 1194 - 1194

Опубликована: Март 8, 2019

The extracellular signal-regulated kinases 1/2 (ERK) are central signaling components that regulate stimulated cellular processes such as proliferation and differentiation. When dysregulated, these participate in the induction maintenance of various pathologies, primarily cancer. While ERK is localized cytoplasm resting cells, many its substrates nuclear, indeed, stimulation induces a rapid robust nuclear translocation ERK. Similarly to other shuttle nucleus upon stimulation, does not use canonical importinα/β mechanism translocation. Rather, it has own unique signal (NTS) interacts with importin7 allow shuttling via pores. Prevention inhibits B-Raf- N/K-Ras-transformed cancers. This effect distinct from one achieved by catalytic Raf MEK inhibitors used clinically, cells treated develop resistance much more slowly. In this review, we describe translocation, present all substrates, discuss role cancer compare components. We also proof principle data for an anti-cancer target. It likely prevention will eventually serve way combat Ras transformed cancers less side-effects than currently drugs.

Язык: Английский

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Exploring receptor tyrosine kinases-inhibitors in Cancer treatments

Egyptian Journal of Medical Human Genetics, Год журнала: 2019, Номер 20(1)

Опубликована: Дек. 1, 2019

Abstract Background Receptor tyrosine kinases (RTKs) are signaling enzymes responsible for the transfer of Adenosine triphosphate (ATP) γ-phosphate to residues substrates. RTKs demonstrate essential roles in cellular growth, metabolism, differentiation, and motility. Anomalous expression RTK customarily leads cell growth dysfunction, which is connected tumor takeover, angiogenesis, metastasis. Understanding structure, mechanisms adaptive acquired resistance, optimizing inhibition RTKs, eradicating cum minimizing havocs quiescence cancer cells paramount. MainText Tyrosine kinase inhibitors (TKIs) vie with ATP-binding site ATP hitherto reduce phosphorylation, thus hampering cells. TKIs can either be monoclonal antibodies that compete receptor’s extracellular domain or small molecules inhibit prevent conformational changes activate RTKs. Progression related aberrant activation due mutation, excessive expression, autocrine stimulation. Conclusions modes structures germane design novel potent TKIs. This review shed light on kinases, receptor inhibitors, imatinib associated toxicities, optimization curtailing prospects based treatments.

Язык: Английский

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Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(11), С. 6047 - 6047

Опубликована: Июнь 3, 2021

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2-like (CLK1-4) belong to the CMGC group of serine/threonine kinases. These protein are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cycle control, differentiation, homocysteine/methionine/folate regulation, body temperature endocytosis, neuronal development, synaptic plasticity, etc. Abnormal expression and/or activity some these kinases, DYRK1A particular, is seen many human nervous system diseases, such as cognitive deficits associated with Down syndrome, Alzheimer’s disease related tauopathies, dementia, Pick’s disease, Parkinson’s other neurodegenerative Phelan-McDermid autism, CDKL5 deficiency disorder. DYRKs CLKs also diabetes, abnormal folate/methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast, pancreatic cancers) leukemias (acute lymphoblastic leukemia, acute megakaryoblastic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), well caused by unicellular parasites (Leishmania, Trypanosoma, Plasmodium). This variety pathological implications calls for (1) a better understanding regulations substrates (2) development potent selective inhibitors their evaluation therapeutic drugs. article briefly reviews current knowledge about DYRK/CLK disease.

Язык: Английский

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The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities

Cancers, Год журнала: 2020, Номер 12(8), С. 2106 - 2106

Опубликована: Июль 29, 2020

DYRK (dual-specificity tyrosine-regulated kinases) are an evolutionary conserved family of protein kinases with members from yeast to humans. In humans, DYRKs pleiotropic factors that phosphorylate a broad set proteins involved in many different cellular processes. These include have been associated all the hallmarks cancer, genomic instability increased proliferation and resistance, programmed cell death, or signaling pathways whose dysfunction is relevant tumor onset progression. accordance involvement regulation tumorigenic processes, increasing number research studies published recent years showing either alterations gene expression samples and/or providing evidence DYRK-dependent mechanisms contribute initiation present article, we will review current understanding role cancer progression, overview small molecules act as inhibitors discussing clinical implications therapeutic opportunities currently available.

Язык: Английский

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Causal interactions from proteomic profiles: Molecular data meet pathway knowledge

Patterns, Год журнала: 2021, Номер 2(6), С. 100257 - 100257

Опубликована: Май 12, 2021

We present a computational method to infer causal mechanisms in cell biology by analyzing changes high-throughput proteomic profiles on the background of prior knowledge captured biochemical reaction bases. The mimics biologist's traditional approach explaining data using but does this at scale hundreds thousands reactions. This is specific example how automate scientific reasoning processes and illustrates power mapping from experimental via logic programming. identified can explain physiological perturbations, propagating network reactions, affect cellular responses their phenotypic consequences. Causal pathway analysis powerful flexible discovery tool for wide range profiling types biological questions. automated causation inference tool, as well source code, are freely available http://causalpath.org.

Язык: Английский

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The chromosome 21 kinase DYRK1A: emerging roles in cancer biology and potential as a therapeutic target

Oncogene, Год журнала: 2022, Номер 41(14), С. 2003 - 2011

Опубликована: Фев. 26, 2022

Язык: Английский

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Quiescent Cancer Cells—A Potential Therapeutic Target to Overcome Tumor Resistance and Relapse

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(4), С. 3762 - 3762

Опубликована: Фев. 13, 2023

Quiescent cancer cells (QCCs) are nonproliferating arrested in the G0 phase, characterized by ki67low and p27high. QCCs avoid most chemotherapies, some treatments could further lead to a higher proportion of tumors. also associated with recurrence since they can re-enter proliferative state when conditions favorable. As drug resistance tumor recurrence, there is great need understand characteristics QCCs, decipher mechanisms that regulate proliferative-quiescent transition cells, develop new strategies eliminate residing solid In this review, we discussed QCC-induced recurrence. We therapeutic overcome relapse targeting including (i) identifying reactive quiescent removing them via cell-cycle-dependent anticancer reagents; (ii) modulating quiescence-to-proliferation switch; (iii) eliminating their unique features. It believed simultaneous co-targeting proliferating may ultimately development more effective for treatment

Язык: Английский

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Reverse cardio-oncology: Exploring the effects of cardiovascular disease on cancer pathogenesis

Journal of Molecular and Cellular Cardiology, Год журнала: 2021, Номер 163, С. 1 - 8

Опубликована: Сен. 27, 2021

Язык: Английский

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Serum deprivation initiates adaptation and survival to oxidative stress in prostate cancer cells

Scientific Reports, Год журнала: 2020, Номер 10(1)

Опубликована: Июль 27, 2020

Abstract Inadequate nutrient intake leads to oxidative stress disrupting homeostasis, activating signaling, and altering metabolism. Oxidative serves as a hallmark in developing prostate lesions, an aggressive cancer phenotype mechanisms allowing cells adapt survive. It is unclear how adaptation survival are facilitated; however, literature across several organisms demonstrates that reversible cellular growth arrest the transcription factor, nuclear factor-kappaB (NF-κB), contribute cell therapeutic resistance under stress. We examined adaptability following deprivation three models displaying varying degrees of tumorigenicity. observed reducing serum (starved) induced reactive oxygen species which provided early environment allowed confer increased (H 2 O ). Measurement viability demonstrated low death profile stressed (starved + H ), while proliferation was stagnant. Quantitative measurement apoptosis showed no significant suggesting adaptive mechanism tolerate Stressed also presented quiescent phenotype, correlating with NF-κB translocation, tolerance. Our data suggests primes for and/or general anti-tumorigenic agents.

Язык: Английский

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DREAM On: Cell Cycle Control in Development and Disease

Annual Review of Genetics, Год журнала: 2021, Номер 55(1), С. 309 - 329

Опубликована: Сен. 9, 2021

Perfectly orchestrated periodic gene expression during cell cycle progression is essential for maintaining genome integrity and ensuring that proliferation can be stopped by environmental signals. Genetic proteomic studies the past two decades revealed remarkable evolutionary conservation of key mechanisms control cycle-regulated expression, including multisubunit DNA-binding DREAM complexes. complexes containing a retinoblastoma family member, an E2F transcription factor its dimerization partner, five proteins related to products Caenorhabditis elegans multivulva (Muv) class B genes lin-9, lin-37, lin-52, lin-53, lin-54 (comprising MuvB core) have been described in diverse organisms, from worms humans. This review summarizes current knowledge structure, function, regulation different as well role human disease.

Язык: Английский

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