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

2019 ◽  
Vol 20 (5) ◽  
pp. 1194 ◽  
Author(s):  
Galia Maik-Rachline ◽  
Avital Hacohen-Lev-Ran ◽  
Rony Seger
Keyword(s):  
Nuclear Translocation ◽  
Resting Cells ◽  
Nuclear Pores ◽  
Cellular Processes ◽  
Extracellular Signal ◽  
Anti Cancer ◽  
Proliferation And Differentiation ◽  
The One ◽  
Signaling Components ◽  
Proof Of Principle

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

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

2018 ◽  
Vol 108 (2) ◽  
pp. 121-131 ◽  
Author(s):  
Karen Flores ◽  
Suresh Singh Yadav ◽  
Arieh A. Katz ◽  
Rony Seger
Keyword(s):  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Processes ◽  
Development Of Resistance ◽  
Mapk Cascades ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Importin Α ◽  
Cancer And Inflammation

The mitogen-activated protein kinase (MAPK) cascades are central signaling pathways that play a central role in the regulation of most stimulated cellular processes including proliferation, differentiation, stress response and apoptosis. Currently 4 such cascades are known, each termed by its downstream MAPK components: the extracellular signal-regulated kinase 1/2 (ERK1/2), cJun-N-terminal kinase (JNK), p38 and ERK5. One of the hallmarks of these cascades is the stimulated nuclear translocation of their MAPK components using distinct mechanisms. ERK1/2 are shuttled into the nucleus by importin7, JNK and p38 by a dimer of importin3 with either importin9 or importin7, and ERK5 by importin-α/β. Dysregulation of these cascades often results in diseases, including cancer and inflammation, as well as developmental and neurological disorders. Much effort has been invested over the years in developing inhibitors to the MAPK cascades to combat these diseases. Although some inhibitors are already in clinical use or clinical trials, their effects are hampered by development of resistance or adverse side-effects. Recently, our group developed 2 myristoylated peptides: EPE peptide, which inhibits the interaction of ERK1/2 with importin7, and PERY peptide, which prevents JNK/p38 interaction with either importin7 or importin9. These peptides block the nuclear translocation of their corresponding kinases, resulting in prevention of several cancers, while the PERY peptide also inhibits inflammation-induced diseases. These peptides provide a proof of concept for the use of the nuclear translocation of MAPKs as therapeutic targets for cancer and/or inflammation.

scholarly journals The Long-Lasting Protective Effect of HGF in Cardiomyoblasts Exposed to Doxorubicin Requires a Positive Feed-Forward Loop Mediated by Erk1,2-Timp1-Stat3

2020 ◽  
Vol 21 (15) ◽  
pp. 5258
Author(s):  
Simona Gallo ◽  
Martina Spilinga ◽  
Elena Casanova ◽  
Alessandro Bonzano ◽  
Carla Boccaccio ◽  
...  
Keyword(s):  
Protective Effect ◽  
Nuclear Translocation ◽  
Genotoxic Stress ◽  
Feed Forward ◽  
Histone H2ax ◽  
Feed Forward Loop ◽  
Stat3 Signaling ◽  
Extracellular Signal ◽  
Anti Cancer ◽  
H9c2 Cardiomyoblasts

Previous studies showed that the hepatocyte growth factor (HGF)–Met receptor axis plays long-lasting cardioprotection against doxorubicin anti-cancer therapy. Here, we explored the mechanism(s) underlying the HGF protective effect. DNA damage was monitored by histone H2AX phosphorylation and apoptosis by proteolytic cleavage of caspase 3. In doxorubicin-treated H9c2 cardiomyoblasts, the long-lasting cardioprotection is mediated by activation of the Ras/Raf/Mek/Erk (extracellular signal-regulated kinase 1,2) signaling pathway and requires Stat3 (signal transducer and activator of transcription 3) activation. The HGF protection was abrogated by the Erk1,2 inhibitor, PD98059. This translated into reduced Y705 phosphorylation and impaired nuclear translocation of Stat3, showing crosstalk between Erk1,2 and Stat3 signaling. An array of 29 cytokines, known to activate Stat3, was interrogated to identify the molecule(s) linking the two pathways. The analysis showed a selective increase in expression of the tissue inhibitor of metalloproteinases-1 (Timp1). Consistently, inhibition in cardiomyoblasts of Timp1 translation by siRNAs blunted both Stat3 activation and the cardioprotective effect of HGF. Thus, Timp1 is responsible for the generation of a feed-forward loop of Stat3 activation and helps cardiomyocytes to survive during the genotoxic stress induced by anthracyclines.

scholarly journals Gq-Induced Apoptosis is Mediated by AKT Inhibition That Leads to PKC-Induced JNK Activation

2018 ◽  
Vol 50 (1) ◽  
pp. 121-135 ◽  
Author(s):  
Guy Nadel ◽  
Zhong Yao ◽  
Ido Ben-Ami ◽  
Zvi Naor ◽  
Rony Seger
Keyword(s):  
Inhibitory Effect ◽  
General Mechanism ◽  
Prostate Cancer Cells ◽  
Cellular Processes ◽  
Proliferation And Differentiation ◽  
Induced Apoptosis ◽  
Jnk Activation ◽  
Jnk Cascade ◽  
Signaling Components ◽  
Pkc Activation

Background/Aims: Gq protein-coupled receptors (GqPCRs) regulate various cellular processes including mainly proliferation and differentiation. In a previous study, we found that in prostate cancer cells, the GqPCR of GnRH induces apoptosis by reducing the PKC-dependent AKT activity and elevating JNK phosphorylation. Since it was thought that GqPCR induces mainly activation of AKT, we undertook to examine how general is this phenomenon and understand its signaling. Methods: We used various cells to follow the phosphorylation of signaling components using western blotting. Results: In a screen of 21 cell lines, we found that PKC activation results in the reduction of AKT activity, which correlates nicely to JNK activation and in some cases to apoptosis. To further understand the signaling pathways involved in this stimulation, we studied in detail the SVOG-4O and αT3-1 cells. We found that PGF2α and GnRH agonist (GnRH-a) indeed induce significant Gq- and PKC- dependent apoptosis in these cells. This is mediated by two signaling branches downstream of PKC, which converge at the level of MLK3 upstream of JNK. One branch consists on c-Src activation of the JNK cascade and the second involves reduction of AKT activity that alleviates its inhibitory effect on MLK3, to allow the flow of the c-Src signal to JNK. At the MAPKK level, we found that the signal is transmitted by MKK7 and not MKK4. Conclusion: Our results present a general mechanism that mediates a GqPCR-induced, death receptors-independent, apoptosis in physiological, as well as cancer-related systems.

scholarly journals Spatial and temporal signal processing and decision making by MAPK pathways

2017 ◽  
Vol 216 (2) ◽  
pp. 317-330 ◽  
Author(s):  
Oguzhan Atay ◽  
Jan M. Skotheim
Keyword(s):  
Signal Processing ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Cell Physiology ◽  
Cellular Processes ◽  
Mapk Pathways ◽  
Extracellular Signal ◽  
Proliferation And Differentiation ◽  
Mitogen Activated Protein ◽  
Recent Developments

Mitogen-activated protein kinase (MAPK) pathways are conserved from yeast to man and regulate a variety of cellular processes, including proliferation and differentiation. Recent developments show how MAPK pathways perform exquisite spatial and temporal signal processing and underscores the importance of studying the dynamics of signaling pathways to understand their physiological response. The importance of dynamic mechanisms that process input signals into graded downstream responses has been demonstrated in the pheromone-induced and osmotic stress–induced MAPK pathways in yeast and in the mammalian extracellular signal-regulated kinase MAPK pathway. Particularly, recent studies in the yeast pheromone response have shown how positive feedback generates switches, negative feedback enables gradient detection, and coherent feedforward regulation underlies cellular memory. More generally, a new wave of quantitative single-cell studies has begun to elucidate how signaling dynamics determine cell physiology and represents a paradigm shift from descriptive to predictive biology.

scholarly journals Bromamine T (BAT) Exerts Stronger Anti-Cancer Properties than Taurine (Tau)

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 182
Author(s):  
Stella Baliou ◽  
Maria Goulielmaki ◽  
Petros Ioannou ◽  
Christina Cheimonidi ◽  
Ioannis P. Trougakos ◽  
...  
Keyword(s):  
Cytotoxic Effect ◽  
Human Colon ◽  
Mitogen Activated Protein Kinase ◽  
Mitochondrial Apoptosis ◽  
Therapeutic Modalities ◽  
Cancer Pathogenesis ◽  
Extracellular Signal ◽  
Anti Cancer ◽  
Mitogen Activated Protein

Background: Taurine (Tau) ameliorates cancer pathogenesis. Researchers have focused on the functional properties of bromamine T (BAT), a stable active bromine molecule. Both N-bromotaurine (TauNHBr) and BAT exert potent anti-inflammatory properties, but the landscape remains obscure concerning the anti-cancer effect of BAT. Methods: We used Crystal Violet, colony formation, flow cytometry and Western blot experiments to evaluate the effect of BAT and Tau on the apoptosis and autophagy of cancer cells. Xenograft experiments were used to determine the in vivo cytotoxicity of either agent. Results: We demonstrated that both BAT and Tau inhibited the growth of human colon, breast, cervical and skin cancer cell lines. Among them, BAT exerted the greatest cytotoxic effect on both RKO and MDA-MB-468 cells. In particular, BAT increased the phosphorylation of c-Jun N-terminal kinases (JNK½), p38 mitogen-activated protein kinase (MAPK), and extracellular-signal-regulated kinases (ERK½), thereby inducing mitochondrial apoptosis and autophagy in RKO cells. In contrast, Tau exerted its cytotoxic effect by upregulating JNK½ forms, thus triggering mitochondrial apoptosis in RKO cells. Accordingly, colon cancer growth was impaired in vivo. Conclusions: BAT and Tau exerted their anti-tumor properties through the induction of (i) mitochondrial apoptosis, (ii) the MAPK family, and iii) autophagy, providing novel anti-cancer therapeutic modalities.

scholarly journals Nucleocytoplasmic Shuttling of Endocytic Proteins

2001 ◽  
Vol 153 (7) ◽  
pp. 1511-1518 ◽  
Author(s):  
Manuela Vecchi ◽  
Simona Polo ◽  
Viviane Poupon ◽  
Jan-Willem van de Loo ◽  
Alexandre Benmerah ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Nuclear Export ◽  
Myeloid Leukemia ◽  
Nuclear Translocation ◽  
Initial Rate ◽  
Nucleocytoplasmic Shuttling ◽  
Cellular Processes ◽  
Transactivation Assay ◽  
Ordered Assembly ◽  
Endocytic Proteins

Many cellular processes rely on the ordered assembly of macromolecular structures. Here, we uncover an unexpected link between two such processes, endocytosis and transcription. Many endocytic proteins, including eps15, epsin1, the clathrin assembly lymphoid myeloid leukemia (CALM), and α-adaptin, accumulate in the nucleus when nuclear export is inhibited. Endocytosis and nucleocytoplasmic shuttling of endocytic proteins are apparently independent processes, since inhibition of endocytosis did not appreciably alter nuclear translocation of endocytic proteins, and blockade of nuclear export did not change the initial rate of endocytosis. In the nucleus, eps15 and CALM acted as positive modulators of transcription in a GAL4-based transactivation assay, thus raising the intriguing possibility that some endocytic proteins play a direct or indirect role in transcriptional regulation.

Measuring Absolute Membrane Potential Across Space and Time

2021 ◽  
Vol 50 (1) ◽  
Author(s):  
Julia R. Lazzari-Dean ◽  
Anneliese M.M. Gest ◽  
Evan W. Miller
Keyword(s):  
Membrane Potential ◽  
Neurotransmitter Release ◽  
Cell Cycle Control ◽  
The Other ◽  
Annual Review ◽  
Publication Date ◽  
Short Term ◽  
Cellular Processes ◽  
Sensing Platform ◽  
The One

Membrane potential (Vmem) is a fundamental biophysical signal present in all cells. Vmem signals range in time from milliseconds to days, and they span lengths from microns to centimeters. Vmem affects many cellular processes, ranging from neurotransmitter release to cell cycle control to tissue patterning. However, existing tools are not suitable for Vmem quantification in many of these areas. In this review, we outline the diverse biology of Vmem, drafting a wish list of features for a Vmem sensing platform. We then use these guidelines to discuss electrode-based and optical platforms for interrogating Vmem. On the one hand, electrode-based strategies exhibit excellent quantification but are most effective in short-term, cellular recordings. On the other hand, optical strategies provide easier access to diverse samples but generally only detect relative changes in Vmem. By combining the respective strengths of these technologies, recent advances in optical quantification of absolute Vmem enable new inquiries into Vmem biology. Expected final online publication date for the Annual Review of Biophysics, Volume 50 is May 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Polycomb genes role in cancer pathophysiology is offering targets for therapeutics including gene therapy

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Catalytic Activity ◽  
Detailed Understanding ◽  
The Core ◽  
Chromatin Regulators ◽  
Genetic Modifications ◽  
Anti Cancer ◽  
The Many ◽  
The One ◽  
Context Specific ◽  
Study Context

Several phenotypes can come from transcription regulation. Sequence-specific transcription factors are needed to effectively execute transcriptional programs, however they are often not operating alone. Polycomb PcG proteins are a well-known class of chromatin regulators found in Drosophila melanogaster and other species, including humans. As time passed, the concept of a PCG gene or protein shifted from the original phenotypic meaning of mutant flies to the contemporary biochemical description. PCG genes and proteins are under investigation for their critical contributions to physiology and their cancer treatment potential. Adding additional PcG members, with substantial responsibilities in PRC modulation, has opened new routes of inquiry in the issue. It is still needed to discover the many PRC variations' roles and how their catalytic activity is controlled. This review covers mutually exclusive PRC2 variants and employs a technique like the one used for PRC1 variants. Based on current biochemical findings, these classifications are valid. More auxiliary PcG subunit research is needed for now. Moreover, it is unknown how many PRC cell variations occur (hypothetically, there could be more than 100 different PRC variants).In order to fully elucidate the new PcG proteins and complexes, it is necessary to perform comprehensive research. We must study context-specific genetic modifications to better provide remedies. Current anti-cancer drugs target mainly the core subunits and catalytic activity of PRC2 and PRC1, and understanding these functions is critical. Targeting each particular activity that has been deregulated might be rather beneficial. PCG proteins are involved in oncogenesis, tumor suppression, and development/congenital illness as well. PcG involvement in cancer, once revealed, would be intriguing. Successful and effective therapeutic therapies will be helped by a detailed understanding of the pathways that contain PcG proteins.

MAPK Cascades in Cell Growth and Death

Physiology ◽  
1997 ◽  
Vol 12 (6) ◽  
pp. 286-293 ◽  
Author(s):  
JT Neary
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Cellular Proliferation ◽  
Inflammatory Diseases ◽  
Growth Arrest ◽  
Therapeutic Strategies ◽  
Extracellular Signals ◽  
Mapk Cascades ◽  
Proliferation And Differentiation ◽  
Signaling Components

Distinct signal transduction cascades comprised of at least three proteinkinases mediate cellular proliferation and differentiation, growth arrest, and programmed cell death. These cytosolic enzymes relay extracellular signals from cell surface to nucleus, leading to changes in gene expression. Signaling components of these cascades offer new possibilities for therapeutic strategies in tumorigenesis, inflammatory diseases, immunopotentiation, wound healing, and regeneration.

Sign in / Sign up

Export Citation Format

Share Document