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International Journal of Molecular... Jul 2021The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid... (Review)
Review
The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway.
Topics: Animals; Atherosclerosis; Humans; MAP Kinase Kinase 5; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 7; Neoplasms
PubMed: 34299213
DOI: 10.3390/ijms22147594 -
Biochemistry and Cell Biology =... Jun 2023The mitogen- and stress-activated protein kinases (MSK) are epigenetic modifiers that regulate gene expression in normal and disease cell states. MSK1 and 2 are involved... (Review)
Review
The mitogen- and stress-activated protein kinases (MSK) are epigenetic modifiers that regulate gene expression in normal and disease cell states. MSK1 and 2 are involved in a chain of signal transduction events bringing signals from the external environment of a cell to specific sites in the genome. MSK1/2 phosphorylate histone H3 at multiple sites, resulting in chromatin remodeling at regulatory elements of target genes and the induction of gene expression. Several transcription factors (RELA of NF-κB and CREB) are also phosphorylated by MSK1/2 and contribute to induction of gene expression. In response to signal transduction pathways, MSK1/2 can stimulate genes involved in cell proliferation, inflammation, innate immunity, neuronal function, and neoplastic transformation. Abrogation of the MSK-involved signaling pathway is among the mechanisms by which pathogenic bacteria subdue the host's innate immunity. Depending on the signal transduction pathways in play and the MSK-targeted genes, MSK may promote or hinder metastasis. Thus, depending on the type of cancer and genes involved, MSK overexpression may be a good or poor prognostic factor. In this review, we focus on mechanisms by which MSK1/2 regulate gene expression, and recent studies on their roles in normal and diseased cells.
Topics: Gene Expression; Histones; Mitogens; Phosphorylation; Protein Kinases; Humans; Animals
PubMed: 36812480
DOI: 10.1139/bcb-2022-0371 -
Clinical Cancer Research : An Official... Aug 2019Targeted next-generation sequencing of DNA has become more widely used in the management of patients with lung adenocarcinoma; however, no clear mitogenic driver...
High Yield of RNA Sequencing for Targetable Kinase Fusions in Lung Adenocarcinomas with No Mitogenic Driver Alteration Detected by DNA Sequencing and Low Tumor Mutation Burden.
PURPOSE
Targeted next-generation sequencing of DNA has become more widely used in the management of patients with lung adenocarcinoma; however, no clear mitogenic driver alteration is found in some cases. We evaluated the incremental benefit of targeted RNA sequencing (RNAseq) in the identification of gene fusions and exon 14 (ex14) alterations in DNA sequencing (DNAseq) driver-negative lung cancers.
EXPERIMENTAL DESIGN
Lung cancers driver negative by MSK-IMPACT underwent further analysis using a custom RNAseq panel (MSK-Fusion). Tumor mutation burden (TMB) was assessed as a potential prioritization criterion for targeted RNAseq.
RESULTS
As part of prospective clinical genomic testing, we profiled 2,522 lung adenocarcinomas using MSK-IMPACT, which identified 195 (7.7%) fusions and 119 (4.7%) ex14 alterations. Among 275 driver-negative cases with available tissue, 254 (92%) had sufficient material for RNAseq. A previously undetected alteration was identified in 14% (36/254) of cases, 33 of which were actionable (27 in-frame fusions, 6 ex14). Of these 33 patients, 10 then received matched targeted therapy, which achieved clinical benefit in 8 (80%). In the 32% (81/254) of DNAseq driver-negative cases with low TMB [0-5 mutations/Megabase (mut/Mb)], 25 (31%) were positive for previously undetected gene fusions on RNAseq, whereas, in 151 cases with TMB >5 mut/Mb, only 7% were positive for fusions ( < 0.0001).
CONCLUSIONS
Targeted RNAseq assays should be used in all cases that appear driver negative by DNAseq assays to ensure comprehensive detection of actionable gene rearrangements. Furthermore, we observed a significant enrichment for fusions in DNAseq driver-negative samples with low TMB, supporting the prioritization of such cases for additional RNAseq..
Topics: Adenocarcinoma of Lung; Humans; Lung Neoplasms; Mitogens; Mutation; Prospective Studies; Sequence Analysis, DNA; Sequence Analysis, RNA
PubMed: 31028088
DOI: 10.1158/1078-0432.CCR-19-0225 -
Journal of Hepatology Feb 2024Hepatocyte apoptosis, a well-defined form of cell death in non-alcoholic steatohepatitis (NASH), is considered the primary cause of liver inflammation and fibrosis....
BACKGROUND & AIMS
Hepatocyte apoptosis, a well-defined form of cell death in non-alcoholic steatohepatitis (NASH), is considered the primary cause of liver inflammation and fibrosis. However, the mechanisms underlying the regulation of hepatocyte apoptosis in NASH remain largely unclear. We explored the anti-apoptotic effect of hepatocyte CD1d in NASH.
METHODS
Hepatocyte CD1d expression was analyzed in patients with NASH and mouse models. Hepatocyte-specific gene overexpression or knockdown and anti-CD1d crosslinking were used to investigate the anti-apoptotic effect of hepatocyte CD1d on lipotoxicity-, Fas-, and concanavalin (ConA)-mediated liver injuries. A high-fat diet, a methionine-choline-deficient diet, a Fas agonist, and ConA were used to induce lipotoxic and/or apoptotic liver injuries. Palmitic acid was used to mimic lipotoxicity-induced apoptosis in vitro.
RESULTS
We identified a dramatic decrease in CD1d expression in hepatocytes of patients with NASH and mouse models. Hepatocyte-specific CD1d overexpression and knockdown experiments collectively demonstrated that hepatocyte CD1d protected against hepatocyte apoptosis and alleviated hepatic inflammation and injuries in NASH mice. Furthermore, decreased JAK2-STAT3 signaling was observed in NASH patient livers. Mechanistically, anti-CD1d crosslinking on hepatocytes induced tyrosine phosphorylation of the CD1d cytoplasmic tail, leading to the recruitment and phosphorylation of JAK2. Phosphorylated JAK2 activated STAT3 and subsequently reduced apoptosis in hepatocytes, which was associated with an increase in anti-apoptotic effectors (Bcl-xL and Mcl-1) and a decrease in pro-apoptotic effectors (cleaved-caspase 3/7). Moreover, anti-CD1d crosslinking effectively protected against Fas- or ConA-mediated hepatocyte apoptosis and liver injury in mice.
CONCLUSIONS
Our study uncovered a previously unrecognized anti-apoptotic CD1d-JAK2-STAT3 axis in hepatocytes that conferred hepatoprotection and highlighted the potential of hepatocyte CD1d-directed therapy for liver injury and fibrosis in NASH, as well as in other liver diseases associated with hepatocyte apoptosis.
IMPACT AND IMPLICATIONS
Excessive and/or sustained hepatocyte apoptosis is critical in driving liver inflammation and injury. The mechanisms underlying the regulation of hepatocyte apoptosis in non-alcoholic steatohepatitis (NASH) remain largely unclear. Here, we found that CD1d expression in hepatocytes substantially decreases and negatively correlates with the severity of liver injury in patients with NASH. We further revealed a previously unrecognized anti-apoptotic CD1d-JAK2-STAT3 signaling axis in hepatocytes, which confers significant protection against liver injury in NASH and acute liver diseases. Thus, hepatocyte CD1d-targeted therapy could be a promising strategy to manipulate liver injury in both NASH and other hepatocyte apoptosis-related liver diseases.
Topics: Animals; Humans; Mice; Apoptosis; Concanavalin A; Disease Models, Animal; Hepatocytes; Inflammation; Non-alcoholic Fatty Liver Disease
PubMed: 38438948
DOI: 10.1016/j.jhep.2023.10.025 -
Blood Apr 2023
Topics: Humans; Mitogens; Folklore; Aging; Cell Cycle Checkpoints; Cell Proliferation
PubMed: 37079334
DOI: 10.1182/blood.2023019780 -
Proceedings of the National Academy of... Jun 2023The balance between neural stem cell proliferation and neuronal differentiation is paramount for the appropriate development of the nervous system. Sonic hedgehog (Shh)...
The balance between neural stem cell proliferation and neuronal differentiation is paramount for the appropriate development of the nervous system. Sonic hedgehog (Shh) is known to sequentially promote cell proliferation and specification of neuronal phenotypes, but the signaling mechanisms responsible for the developmental switch from mitogenic to neurogenic have remained unclear. Here, we show that Shh enhances Ca activity at the neural cell primary cilium of developing embryos through Ca influx via transient receptor potential cation channel subfamily C member 3 (TRPC3) and release from intracellular stores in a developmental stage-dependent manner. This ciliary Ca activity in turn antagonizes canonical, proliferative Shh signaling in neural stem cells by down-regulating Sox2 expression and up-regulating expression of neurogenic genes, enabling neuronal differentiation. These discoveries indicate that the Shh-Ca-dependent switch in neural cell ciliary signaling triggers the switch in Shh action from canonical-mitogenic to neurogenic. The molecular mechanisms identified in this neurogenic signaling axis are potential targets for the treatment of brain tumors and neurodevelopmental disorders.
Topics: Calcium; Cell Differentiation; Cilia; Hedgehog Proteins; Neural Tube; Neurogenesis; Xenopus laevis; Animals; Xenopus Proteins
PubMed: 37252980
DOI: 10.1073/pnas.2220037120 -
International Journal of Molecular... Mar 2022Mitogen-activated protein kinases (MAPKs) form tightly controlled signaling cascades that play essential roles in plant growth, development, and defense response.... (Review)
Review
Mitogen-activated protein kinases (MAPKs) form tightly controlled signaling cascades that play essential roles in plant growth, development, and defense response. However, the molecular mechanisms underlying MAPK cascades are still very elusive, largely because of our poor understanding of how they relay the signals. The MAPK cascade is composed of MAPK, MAPKK, and MAPKKK. They transfer signals through the phosphorylation of MAPKKK, MAPKK, and MAPK in turn. MAPKs are organized into a complex network for efficient transmission of specific stimuli. This review summarizes the research progress in recent years on the classification and functions of MAPK cascades under various conditions in plants, especially the research status and general methods available for identifying MAPK substrates, and provides suggestions for future research directions.
Topics: MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Plant Development
PubMed: 35269886
DOI: 10.3390/ijms23052744 -
The Oncologist Oct 2022Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4 and 6) are approved for the treatment of subsets of patients with hormone receptor positive (HR+)... (Review)
Review
Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4 and 6) are approved for the treatment of subsets of patients with hormone receptor positive (HR+) breast cancer (BC). In metastatic disease, strategies involving endocrine therapy combined with CDK4 and 6 inhibitors (CDK4 and 6i) improve clinical outcomes in HR+ BCs. CDK4 and 6i prevent retinoblastoma tumor suppressor protein phosphorylation, thereby blocking the transcription of E2F target genes, which in turn inhibits both mitogen and estrogen-mediated cell proliferation. In this review, we summarize preclinical data pertaining to the use of CDK4 and 6i in BC, with a particular focus on several of the unique chemical, pharmacologic, and mechanistic properties of abemaciclib. As research efforts elucidate the novel mechanisms underlying abemaciclib activity, potential new applications are being identified. For example, preclinical studies have demonstrated abemaciclib can exert antitumor activity against multiple tumor types and can cross the blood-brain barrier. Abemaciclib has also demonstrated distinct activity as a monotherapeutic in the treatment of BC. Accordingly, we also discuss how a greater understanding of mechanisms related to CDK4 and 6 blockade highlight abemaciclib's unique in-class properties, and could pave new avenues for enhancing its therapeutic efficacy.
Topics: Aminopyridines; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Estrogens; Female; Humans; Mitogens; Protein Kinase Inhibitors; Tumor Suppressor Proteins
PubMed: 35917168
DOI: 10.1093/oncolo/oyac138 -
International Journal of Molecular... Aug 2023Mitogen-activated protein kinase cascades play important roles in various biological programs in plants, including immune responses, but the underlying mechanisms remain...
Mitogen-activated protein kinase cascades play important roles in various biological programs in plants, including immune responses, but the underlying mechanisms remain elusive. Here, we identified the lesion mimic mutant () and determined that the mutant harbored a loss-of-function allele for . developed reddish-brown spots on its leaves at the heading stage, as well as on husks. Compared to the wild type, the mutant exhibited enhanced resistance to the fungal pathogen () and to the bacterial pathogen pv. (). OsMKK6 interacted with OsMPK4 (MITOGEN-ACTIVATED KINASE 4) in vivo, and OsMKK6 phosphorylated OsMPK4 in vitro. The mutant is also a lesion mimic mutant, with reddish-brown spots on its leaves and husks. Pathogen-related genes were significantly upregulated in , and this mutant exhibited enhanced resistance to compared to the wild type. Our results indicate that OsMKK6 and OsMPK4 form a cascade that regulates immune responses in rice.
Topics: Oryza; Disease Resistance; Mitogens; Alleles
PubMed: 37628859
DOI: 10.3390/ijms241612678 -
Veterinarni Medicina May 2022The basic information dealing with the anatomy of the ferret's immune system, cross-reactivity of the ferret leukocytes with polyclonal and monoclonal antibodies ... (Review)
Review
The basic information dealing with the anatomy of the ferret's immune system, cross-reactivity of the ferret leukocytes with polyclonal and monoclonal antibodies and immune response to the mitogens and various infections are presented. The leukocyte numbers in the peripheral blood in the ferrets are lower compared to other species and only one subclass of IgG has been identified in ferrets so far. Lymphocytes make up 12-67% of all the leukocytes in the peripheral blood of the healthy adult ferrets. Lymphocyte subpopulations are similar to other mammals and include T- and B-lymphocytes. T-lymphocytes differentiate into helper (Th) lymphocytes and cytotoxic (Tc) lymphocytes. Currently, ferret granulocytes (CD11), B-lymphocytes (CD79α), T-lymphocytes (CD3), Th-lymphocytes (CD3, CD4), Tc-lymphocytes (CD3, CD8), and CD30, CD45 subpopulations are detected with the use of a number of polyclonal as well as with monoclonal antibodies. In a lymphocyte transformation assay, the mitogen response of the peripheral blood mononuclear cells to concanavalin A (ConA), phytohaemagglutinin (PHA), and pokeweed mitogen (PWM) is the greatest at day 2, 2 and 3, respectively. Serious lymphopenia is observed in ferrets during a distemper infection. A significant decrease in the lymphocyte transformation activity is observed on day 5 and reaches a maximal decrease on days 8-11, with full recovery on days 23-30 after the inoculation of laboratory ferrets with the distemper virus. Ferrets have also been used in studies related to the function of the immune system in infections, Crohn's disease and bronchial asthma.
PubMed: 38716186
DOI: 10.17221/22/2021-VETMED