scholarly journals Anticancer Activities of 9-chloro-6-(piperazin-1-yl)-11H-indeno[1,2-c] quinolin-11-one (SJ10) in Glioblastoma Multiforme (GBM) Chemoradioresistant Cell Cycle-Related Oncogenic Signatures

Cancers ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 262
Author(s):  
Ntlotlang Mokgautsi ◽  
Yu-Cheng Kuo ◽  
Sung-Ling Tang ◽  
Feng-Cheng Liu ◽  
Shiang-Jiun Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Glioblastoma Multiforme ◽  
Target Prediction ◽  
Cyclin B1 ◽  
Cell Cycle Checkpoints ◽  
Mitogen Activated Protein Kinase ◽  
Normal Brain ◽  
Anticancer Activities ◽  
Normal Tissues ◽  
Mitogen Activated Protein

Current anticancer treatments are inefficient against glioblastoma multiforme (GBM), which remains one of the most aggressive and lethal cancers. Evidence has shown the presence of glioblastoma stem cells (GSCs), which are chemoradioresistant and associated with high invasive capabilities in normal brain tissues. Moreover, accumulating studies have indicated that radiotherapy contributes to abnormalities in cell cycle checkpoints, including the G1/S and S phases, which may potentially lead to resistance to radiation. Through computational simulations using bioinformatics, we identified several GBM oncogenes that are involved in regulating the cell cycle. Cyclin B1 (CCNB1) is one of the cell cycle-related genes that was found to be upregulated in GBM. Overexpression of CCNB1 was demonstrated to be associated with higher grades, proliferation, and metastasis of GBM. Additionally, increased expression levels of CCNB1 were reported to regulate activation of mitogen-activated protein kinase 7 (MAPK7) in the G2/M phase, which consequently modulates mitosis; additionally, in clinical settings, MAPK7 was demonstrated to promote resistance to temozolomide (TMZ) and poor patient survival. Therefore, MAPK7 is a potential novel drug target due to its dysregulation and association with TMZ resistance in GBM. Herein, we identified MAPK7/extracellular regulated kinase 5 (ERK5) genes as being overexpressed in GBM tumors compared to normal tissues. Moreover, our analysis revealed increased levels of the cell division control protein homolog (CDC42), a protein which is also involved in regulating the cell cycle through the G1 phase in GBM tissues. This therefore suggests crosstalk among CCNB1/CDC42/MAPK7/cluster of differentiation 44 (CD44) oncogenic signatures in GBM through the cell cycle. We further evaluated a newly synthesized small molecule, SJ10, as a potential target agent of the CCNB1/CDC42/MAPK7/CD44 genes through target prediction tools and found that SJ10 was indeed a target compound for the above-mentioned genes; in addition, it displayed inhibitory activities against these oncogenes as observed from molecular docking analysis.

Parkinson´s related protein DJ-1 is involved in aberrant cell cycle re-entry through Cdk5

2020 ◽  
Author(s):  
Mª José López-Grueso ◽  
Carmen Alicia Padilla ◽  
José Antonio Bárcena ◽  
Raquel Requejo-Aguilar
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cortical Neurons ◽  
Cell Cycle Progression ◽  
Cell Cycle Checkpoints ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Multifunctional Protein ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase

Abstract DJ-1 is a multifunctional protein involved in Parkinson disease (PD) that can act as antioxidant, molecular chaperone, protease, glyoxalase and transcriptional regulator. However, the exact mechanism by which DJ-1 dysfunction contributes to development of Parkinson´s disease remains elusive. Here, using a comparative proteomic analysis between normal cortical neurons and neurons lacking DJ-1, we show that this protein is involved in cell cycle checkpoints disruption as a consequence of increased amount of p-Tau and a-synuclein proteins, altered signalling pathways, as the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK), and deregulation of cyclin-dependent kinase 5 (Cdk5). Cdk5 is normally involved in dendritic growth, axon formation and the establishment of synapses, but can also contribute to cell cycle progression, as in our case, in pathological conditions. In addition, we observed a decrease in proteasomal activity, probably due to Tau phosphorylation that can also lead to activation of mitogenic signalling pathways. Taken together, our findings indicate, for the first time, that aborted cell cycle re-entry could be at the onset of DJ-1 associated PD. Thereby, new approaches targeting cell cycle re-entry can be envisaged to improve current therapeutic strategies.

scholarly journals Confluence of Vascular Endothelial Cells Induces Cell Cycle Exit by Inhibiting p42/p44 Mitogen-Activated Protein Kinase Activity

1999 ◽  
Vol 19 (4) ◽  
pp. 2763-2772 ◽  
Author(s):  
Francesc Viñals ◽  
Jacques Pouysségur
Keyword(s):  
Cell Cycle ◽  
Endothelial Cells ◽  
Growth Factors ◽  
Vascular Endothelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Vascular Endothelial ◽  
Cell Cycle Exit ◽  
Mapk Activation ◽  
Mapk Activity ◽  
Mitogen Activated Protein

ABSTRACT Like other cellular models, endothelial cells in cultures stop growing when they reach confluence, even in the presence of growth factors. In this work, we have studied the effect of cellular contact on the activation of p42/p44 mitogen-activated protein kinase (MAPK) by growth factors in mouse vascular endothelial cells. p42/p44 MAPK activation by fetal calf serum or fibroblast growth factor was restrained in confluent cells in comparison with the activity found in sparse cells. Consequently, the induction of c-fos, MAPK phosphatases 1 and 2 (MKP1/2), and cyclin D1 was also restrained in confluent cells. In contrast, the activation of Ras and MEK-1, two upstream activators of the p42/p44 MAPK cascade, was not impaired when cells attained confluence. Sodium orthovanadate, but not okadaic acid, restored p42/p44 MAPK activity in confluent cells. Moreover, lysates from confluent 1G11 cells more effectively inactivated a dually phosphorylated active p42 MAPK than lysates from sparse cells. These results, together with the fact that vanadate-sensitive phosphatase activity was higher in confluent cells, suggest that phosphatases play a role in the down-regulation of p42/p44 MAPK activity. Enforced long-term activation of p42/p44 MAPK by expression of the chimera ΔRaf-1:ER, which activates the p42/p44 MAPK cascade at the level of Raf, enhanced the expression of MKP1/2 and cyclin D1 and, more importantly, restored the reentry of confluent cells into the cell cycle. Therefore, inhibition of p42/p44 MAPK activation by cell-cell contact is a critical step initiating cell cycle exit in vascular endothelial cells.

scholarly journals Mitogen-Activated Protein Kinase Hog1 Mediates Adaptation to G1 Checkpoint Arrest during Arsenite and Hyperosmotic Stress

2008 ◽  
Vol 7 (8) ◽  
pp. 1309-1317 ◽  
Author(s):  
Iwona Migdal ◽  
Yulia Ilina ◽  
Markus J. Tamás ◽  
Robert Wysocki
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cell Cycle Arrest ◽  
Kinase Inhibitor ◽  
Hyperosmotic Stress ◽  
Mitogen Activated Protein Kinase ◽  
Hog Pathway ◽  
Cycle Arrest ◽  
Mitogen Activated Protein

ABSTRACT Cells slow down cell cycle progression in order to adapt to unfavorable stress conditions. Yeast (Saccharomyces cerevisiae) responds to osmotic stress by triggering G1 and G2 checkpoint delays that are dependent on the mitogen-activated protein kinase (MAPK) Hog1. The high-osmolarity glycerol (HOG) pathway is also activated by arsenite, and the hog1Δ mutant is highly sensitive to arsenite, partly due to increased arsenite influx into hog1Δ cells. Yeast cell cycle regulation in response to arsenite and the role of Hog1 in this process have not yet been analyzed. Here, we found that long-term exposure to arsenite led to transient G1 and G2 delays in wild-type cells, whereas cells that lack the HOG1 gene or are defective in Hog1 kinase activity displayed persistent G1 cell cycle arrest. Elevated levels of intracellular arsenite and “cross talk” between the HOG and pheromone response pathways, observed in arsenite-treated hog1Δ cells, prolonged the G1 delay but did not cause a persistent G1 arrest. In contrast, deletion of the SIC1 gene encoding a cyclin-dependent kinase inhibitor fully suppressed the observed block of G1 exit in hog1Δ cells. Moreover, the Sic1 protein was stabilized in arsenite-treated hog1Δ cells. Interestingly, Sic1-dependent persistent G1 arrest was also observed in hog1Δ cells during hyperosmotic stress. Taken together, our data point to an important role of the Hog1 kinase in adaptation to stress-induced G1 cell cycle arrest.

scholarly journals Expression and modulation of p42/p44 MAPKs and cell cycle regulatory proteins in rat pancreas regeneration

1999 ◽  
Vol 277 (5) ◽  
pp. G953-G959 ◽  
Author(s):  
Jean Morisset ◽  
JoséCristobal Aliaga ◽  
Ezéquiel L. Calvo ◽  
Judith Bourassa ◽  
Nathalie Rivard
Keyword(s):  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Regulatory Proteins ◽  
Mitogen Activated Protein Kinase ◽  
Cyclin Dependent Kinase ◽  
Mapk Activation ◽  
Pancreas Regeneration ◽  
Mitogen Activated Protein ◽  
Cell Cycle Regulatory Proteins

Pancreatic growth occurs after CCK, CCK-induced pancreatitis, and pancreatectomy; the mechanisms involved remain unknown. This study evaluates mitogen-activated protein kinase (MAPK) activation and expression of cell cycle regulatory proteins after pancreatectomy to understand the cellular and molecular mechanisms involved in pancreas regeneration. Rats were killed 1–12 days after pancreatectomy, and p42/p44 MAPK activation, expression of the cyclins D and E, cyclin-dependent kinase (Cdk)-2 activity, retinoblastoma protein (pRb) hyperphosphorylation, and expression of the cyclin kinase inhibitors p15, p21, and p27 were examined. Pancreatic remnants exhibited sustained p42/p44 MAPK activation within 8 h. Cyclins D1 and E showed maximal expression after 2 and 6 days, coinciding with maximal hyperphosphorylation of pRb and Cdk2 activity. The expression of p15 vanished after 12 h, p27 disappeared gradually, and p21 increased early. The p27 complexed with Cdk2 dissociated after 2 days, whereas p21 associated in a reverse fashion. In conclusion, sustained activation of p42/p44 MAPKs and Cdk2 along with overexpression of cyclins D1 and E and reduction of p15 and p27 cyclin inhibitors occurred early after pancreatectomy and are active factors involved in signaling that leads to pancreas regeneration.

Phosphorylation of mitogen-activated protein kinase cascade during early embryo development in the mouse

2000 ◽  
Vol 12 (4) ◽  
pp. 209 ◽  
Author(s):  
Naoki Iwamori ◽  
Kunihiko Naito ◽  
Koji Sugiura ◽  
Hideyuki Kagii ◽  
Masakane Yamashita ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Embryo Development ◽  
Somatic Cells ◽  
Mouse Embryos ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Cell Stage ◽  
Mitogen Activated Protein ◽  
Early Mouse

The mitogen-activated protein kinase (MAPK) cascade is one of the most important signal transduction pathways that regulate the cell cycle in somatic cells. The present study examined the phosphorylation states of components in the MAPK cascade, Raf-1, MEK-1, and extracellular signal regulated kinases (ERKs), which are activated by mitogens, throughout early mouse embryo development and in cultured somatic cells generally. In somatic cells, Raf-1 and MEK-1 were phosphorylated at M-phase and dephosphorylated during interphase. ERKs were not phosphorylated at any stage during the cell cycle. These results were similar to previous findings for the first and second cell cycles of early mouse embryos. In contrast, after the four-cell stage, not only ERKs, but also Raf-1 and MEK-1, were not phosphorylated at any stage during the cell cycle in mouse early embryos. These results suggest that the MAPK cascade in mouse embryos is regulated by the same mechanism as in somatic cells before the two-cell stage, and that regulation is changed to an embryo-specific mechanism after the four-cell stage.

scholarly journals A Novel Mechanism for Mitogen-activated Protein Kinase Localization

2004 ◽  
Vol 15 (10) ◽  
pp. 4457-4466 ◽  
Author(s):  
Eric Bind ◽  
Yelena Kleyner ◽  
Dorota Skowronska-Krawczyk ◽  
Emily Bien ◽  
Brian David Dynlacht ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Subcellular Localization ◽  
Fluorescent Protein ◽  
Nuclear Translocation ◽  
Immunoblot Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Carboxy Terminus ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Mitogen-activated protein kinases/extracellular signal regulated kinases (MAPKs/ERKs) are typically thought to be soluble cytoplasmic enzymes that translocate to the nucleus subsequent to their phosphorylation by their activating kinases or mitogen-activated protein/extracellular signal regulated kinase kinase. We report here the first example of nuclear translocation of a MAPK that occurs via temporally regulated exit from a membranous organelle. Confocal microscopy examining the subcellular localization of ERK3 in several cell lines indicated that this enzyme was targeted to the Golgi/endoplasmic reticulum Golgi intermediate compartment. Deletion analysis of green fluorescent protein (GFP)-ERK3 uncovered a nuclear form that was carboxy-terminally truncated and established a Golgi targeting motif at the carboxy terminus. Immunoblot analysis of cells treated with the proteasome inhibitor MG132 further revealed two cleavage products, suggesting that in vivo, carboxy-terminal cleavage of the full-length protein controls its subcellular localization. In support of this hypothesis, we found that deletion of a small region rich in acidic residues within the carboxy terminus eliminated both the cleavage and nuclear translocation of GFP-ERK3. Finally, cell cycle synchronization studies revealed that the subcellular localization of ERK3 is temporally regulated. These data suggest a novel mechanism for the localization of an MAPK family member, ERK3, in which cell cycle-regulated, site-specific proteolysis generates the nuclear form of the protein.

333 DYNAMICS OF MITOGEN-ACTIVATED PROTEIN KINASE ACTIVITY IN PIG OOCYTES FOLLOWING PARTHENOGENETIC ACTIVATION BY DIFFERENT METHODS

2007 ◽  
Vol 19 (1) ◽  
pp. 282
Author(s):  
L. Nanassy ◽  
K. Lee ◽  
A. Javor ◽  
Z. Machaty
Keyword(s):  
Cell Cycle ◽  
Protein Synthesis ◽  
Protein Kinase ◽  
Kinase Activity ◽  
Mitogen Activated Protein Kinase ◽  
Blastocyst Formation ◽  
Cell Numbers ◽  
Mapk Activity ◽  
Mitogen Activated Protein ◽  
Pronuclear Formation

Cell cycle progression during mitosis and meiosis is known to be regulated by the M-phase promoting factor (MPF). However, recent findings revealed that mitogen-activated protein kinase (MAPK) also plays an important regulatory role during transition through the cell cycle. At fertilization the activity of MAPK drops shortly after MPF inactivation; the objective of this study was to investigate the dynamics of MAPK activity in pig oocytes after different activation methods. In vitro-matured oocytes were allocated to 3 groups. In group 1 (EP), the oocytes were activated by 2 DC pulses of 1.2 kV cm-1, 60 �s each. In the second group (EP + BU), the oocytes were electroporated and incubated for 4 h in 100 �M butyrolactone I (BU, an inhibitor of cdc2 kinase). In group 3 (EP + CHX), the oocytes were electroporated and treated for 5 h with 10 �g mL-1 cycloheximide (CHX, a protein synthesis inhibitor). After electroporation all oocytes were incubated in 7.5 �g mL-1 cytochalasin B for 4 h. Some oocytes were used to determine MAPK activity at 0, 1, 2, 3, 4, 5, and 6 h after electroporation using a MAPK assay kit. The assay measures MAPK activity by determining the phosphorylation of myelin basic protein by MAPK using the transfer of the γ-phosphate of [γ-32P] ATP. Pronuclear formation was evaluated at 6 h after electroporation; blastocyst formation and total cell numbers per embryo were determined after a 7-day culture in PZM-3 medium. Pronuclear formation was compared by the chi-square test, blastocyst formation was assessed using ANOVA, and the kinase activity was evaluated using the Student t-test. Pronuclear formation was highest in the combined methods [69.39% (EP) vs. 86.32% (EP + BU) and 87.56 % (EP + CHX); P < 0.05]. Similarly, the combined methods supported better development to the blastocyst stage [25.06 � 7.96% (EP), 58.32 � 7.62% (EP + BU), and 63.91 � 6.35% (EP + CHX); P < 0.05], whereas the average cell numbers of the blastocysts did not differ (47.11 � 3.12, 46.56 � 2.33, and 44.04 � 1.86, respectively). The initial MAPK activity was 0.123 � 0.017 pmol/min/oocyte which, after 1 h, dropped in all cases to values of 0.069 � 0.009 (EP), 0.072 � 0.007 (EP + BU), and 0.077 � 0.012 (EP + CHX) pmol/min/oocyte (P < 0.05). The MAPK activity in the EP group reached its lowest level at 3 h (0.057 � 0.007 pmol/min/oocyte); however, at 4 h it started to recover and by 6 h the activity (0.079 � 0.022 pmol/min/oocyte) did not differ from that of the non-activated oocytes. In the other groups, MAPK activity stayed low, and by the end of the experimental period it was significantly lower than that in the nontreated metaphase II oocytes (P < 0.05). The results indicate that electroporation followed by protein kinase inhibition or protein synthesis inhibition leads to the efficient inactivation of MAPK activity, and confirm our earlier findings that these combined treatments support superior embryo development after oocyte activation.

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