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The FEBS Journal Jun 2018Cell growth is dictated by a wide range of mitogenic signals, the amplitude and relative contribution of which vary throughout development, differentiation and in a... (Review)
Review
Cell growth is dictated by a wide range of mitogenic signals, the amplitude and relative contribution of which vary throughout development, differentiation and in a tissue-specific manner. The ability to sense and appropriately respond to changes in mitogens is fundamental to control cell growth, and reduced responsiveness of nutrient sensing pathways is widely associated with human disease and ageing. Cellular senescence is an important tumour suppressor mechanism that is characterised by an irreversible exit from the cell cycle in response to replicative exhaustion or excessive DNA damage. Despite the fact that senescent cells can no longer divide, they remain metabolically active and display a range of pro-growth phenotypes that are supported in part by the mTORC1-autophagy signalling axis. As our understanding of the basic mechanisms of controlling mTORC1-autophagy activity and cell growth continues to expand, we are able to explore how changes in nutrient sensing contribute to the acquisition and maintenance of cellular senescence. Furthermore, while the protective effect of senescence to limit cellular transformation is clear, more recently, the age-related accumulation of these pro-inflammatory senescent cells has been shown to contribute to a decline in organismal fitness. We will further discuss whether dysregulation of nutrient sensing pathways can be targeted to promote senescent cell death which would have important implications for healthy ageing.
Topics: Aging; Autophagy; Cell Proliferation; Cellular Senescence; DNA Damage; Genetic Fitness; Humans; Mechanistic Target of Rapamycin Complex 1; Mitogens; Nutrients; Signal Transduction
PubMed: 29405586
DOI: 10.1111/febs.14400 -
Philosophical Transactions of the Royal... Oct 2020Sonic Hedgehog (Shh) Is a critical protein in vertebrate development, orchestrating patterning and growth in many developing systems. First described as a classic... (Review)
Review
Sonic Hedgehog (Shh) Is a critical protein in vertebrate development, orchestrating patterning and growth in many developing systems. First described as a classic morphogen that patterns tissues through a spatial concentration gradient, subsequent studies have revealed a more complex mechanism, in which Shh can also regulate proliferation and differentiation. While the mechanism of action of Shh as a morphogen is well understood, it remains less clear how Shh might integrate patterning, proliferation and differentiation in a given tissue, to ultimately direct its morphogenesis. In tandem with experimental studies, mathematical modelling can help gain mechanistic insights into these processes and bridge the gap between Shh-regulated patterning and growth, by integrating these processes into a common theoretical framework. Here, we briefly review the roles of Shh in vertebrate development, focusing on its functions as a morphogen, mitogen and regulator of differentiation. We then discuss the contributions that modelling has made to our understanding of the action of Shh and highlight current challenges in using mathematical models in a quantitative and predictive way. This article is part of a discussion meeting issue 'Contemporary morphogenesis'.
Topics: Animals; Hedgehog Proteins; Mitogens; Models, Biological; Morphogenesis; Vertebrates
PubMed: 32829689
DOI: 10.1098/rstb.2019.0660 -
Environmental Health Perspectives Dec 1993Liver cell proliferation has often been implicated to play a major role during different steps of the carcinogenic process. Most of the experimental studies indicating a... (Review)
Review
Liver cell proliferation has often been implicated to play a major role during different steps of the carcinogenic process. Most of the experimental studies indicating a close association between cell proliferation and liver cancer development have made use of a compensatory type of proliferative stimulus. However, liver growth may also be caused by direct hyperplasia after administration of primary mitogens. Our recent studies examined the possible differences between these two types of cell proliferation. Our studies indicate that a) increased expression of proto-oncogenes such as c-fos, c-jun, and c-myc is not necessary for entry into the cell cycle during mitogen-induced liver growth; b) mitogen-induced liver growth does not support initiation of chemical hepatocarcinogenesis; c) repeated proliferative stimuli induced by primary mitogens do not stimulate the growth of initiated cells to a focal and/or nodular stage; and d) mitogen-induced liver growth, unlike compensatory regeneration, is followed by a particular mode of cell death, namely, apoptosis. This type of cell death may be responsible for the elimination of carcinogen-initiated cells.
Topics: Animals; Cell Division; Cocarcinogenesis; Gene Expression; Humans; Hyperplasia; Liver; Liver Neoplasms; Liver Neoplasms, Experimental; Liver Regeneration; Mitogens; Proto-Oncogenes; Rats
PubMed: 8013404
DOI: 10.1289/ehp.93101s5163 -
The Yale Journal of Biology and Medicine 1983Mycoplasma arthritidis generates a soluble, non-dialysable, polyclonal mitogen which is active for murine and human T lymphocytes in the presence of an adherent,... (Comparative Study)
Comparative Study Review
Mycoplasma arthritidis generates a soluble, non-dialysable, polyclonal mitogen which is active for murine and human T lymphocytes in the presence of an adherent, radio-resistant, Ia-bearing accessory cell population. Genetic analysis has established that the I-E sub-region of the murine H2 gene complex controls responses to the mitogen and that this control is exercised at the level of the Ia-bearing accessory cell. Lymphocyte proliferation, induction of cytotoxic lymphocytes, and interferon induction are all under Ir gene control and appear to be dependent upon binding of the mitogen to a specific Ia antigen present on a subset of splenic cells. This mycoplasma mitogen provides a new model system to define the mechanisms of Ir gene control of lymphocyte activation.
Topics: Animals; Genes, MHC Class II; H-2 Antigens; Histocompatibility Antigens Class II; Interferon-gamma; Lymphocyte Activation; Macrophage Activation; Mice; Mice, Inbred Strains; Mitogens; Mycoplasma; Rats; Rats, Inbred Strains; T-Lymphocytes
PubMed: 6433573
DOI: No ID Found -
Cold Spring Harbor Perspectives in... Aug 2012Genes dedicated to killing cells must have evolved because of their positive effects on organismal survival. Positive functions of apoptotic genes have been well... (Review)
Review
Genes dedicated to killing cells must have evolved because of their positive effects on organismal survival. Positive functions of apoptotic genes have been well established in a large number of biological contexts, including their role in eliminating damaged and potentially cancerous cells. More recently, evidence has suggested that proapoptotic proteins-mostly caspases-can induce proliferation of neighboring surviving cells to replace dying cells. This process, that we will refer to as "apoptosis-induced proliferation," may be critical for stem cell activity and tissue regeneration. Depending on the caspases involved, at least two distinct types of apoptosis-induced proliferation can be distinguished. One of these types have been studied using a model in which cells have initiated cell death, but are prevented from executing it because of effector caspase inhibition, thereby generating "undead" cells that emit persistent mitogen signaling and overgrowth. Such conditions are likely to contribute to certain forms of cancer. In this review, we summarize the current knowledge of apoptosis-induced proliferation and discuss its relevance for tissue regeneration and cancer.
Topics: Animals; Apoptosis; Caspases; Cell Proliferation; Humans; MAP Kinase Signaling System; Mitogens; Models, Biological; Neoplasms; Regeneration
PubMed: 22855725
DOI: 10.1101/cshperspect.a008797 -
Frontiers in Immunology 2022The expeditious progress of Mesenchymal Stromal Cells (MSC) for therapeutic intervention calls for means to compare differences in potency of cell products. The...
The expeditious progress of Mesenchymal Stromal Cells (MSC) for therapeutic intervention calls for means to compare differences in potency of cell products. The differences may be attributed to innumerable sources including tissue origin, production methods, or even between batches. While the immunomodulatory potential of MSC is recognized and well-documented by an expansive body of evidence, the methodologies and findings vary markedly. In this study, we utilized flowcytometric analysis of lymphocyte proliferation based on cryopreserved peripheral blood mononuclear cells for quantification of the inhibitory effect of MSC. Technical aspects of fluorescent staining and cryopreservation of peripheral blood mononuclear cells were evaluated to obtain optimal results and increase feasibility. A range of common specific and unspecific mitogens was titrated to identify the conditions, in which the effects of Adipose tissue-derived Stromal Cells (ASC; a type of MSC) were most pronounced. Specific stimulation by antibody-mediated activation of CD3 and CD28 TransAct and Dynabeads lead to substantial proliferation of lymphocytes, which was inhibited by ASC. These results were closely mirrored when applying unspecific stimulation in form of phytohemagglutinin (PHA), but not concanavalin A or pokeweed mitogen. The mixed lymphocyte reaction is a common assay which exploits alloreactivity between donors. While arguably more physiologic, the output of the assay often varies substantially, and the extent of proliferation is limited since the frequency of alloreactive cells is low, as opposed to the mitogens. To heighten the proliferative response and robustness, combinations of 2-5 donors were tested. Maximum proliferation was observed when combining 4 or more donors, which was efficiently suppressed by ASC. Several desirable and unfavorable traits can be attributed to the tested stimuli in the form of keywords. The importance of these traits should be scored on a laboratory-level to identify the ideal mitogen. In our case the ranking listed PHA as the most suited candidate. Developing robust assays is no trivial feat. By disclosing the full methodological framework in the present study, we hope to aid others in establishing functional metrics on the road to potency assays.
Topics: Leukocytes, Mononuclear; Cells, Cultured; Mesenchymal Stem Cells; Immunomodulation; Stromal Cells; Mitogens
PubMed: 36578497
DOI: 10.3389/fimmu.2022.1085312 -
Physiological Reports Sep 2021This study characterized the effect of moderate- or vigorous-intensity exercise on leukocyte counts, using fingertip sampling, and mitogen-stimulated oxidative burst,... (Randomized Controlled Trial)
Randomized Controlled Trial
This study characterized the effect of moderate- or vigorous-intensity exercise on leukocyte counts, using fingertip sampling, and mitogen-stimulated oxidative burst, measured in whole blood with a point-of-care test. In a randomized crossover design, 13 healthy adults (mean ± SD age: 22 ± 2 years; seven male, six female) cycled for 30-min, once at 52 ± 5% O and on another occasion at 74 ± 9% O . Blood was sampled at baseline, immediately post-exercise, and 15- and 60-min post-exercise. The leukocyte differential and mitogen-stimulated Reactive Oxygen Species (ROS) production were assessed. Lymphocytes increased immediately post-exercise and decreased below pre-exercise levels 15- and 60-min later. Lymphocyte mobilization immediately post-exercise was 59 ± 36% greater with vigorous- compared to moderate-intensity exercise (p < 0.01). Neutrophils increased immediately after exercise (38 ± 19%, p < 0.01) remaining elevated 60-min later (50 ± 34%, p < 0.01; averaged across intensities) and did not differ between intensities (p = 0.259). Mitogen-stimulated ROS production was amplified immediately (+32 ± 37%, p < 0.01) and 60-min post-exercise (+56 ± 57%, p < 0.01; averaged across intensities) compared to rest and did not differ with intensity (p = 0.739). Exercise-induced amplification of ROS production was abolished when correcting for neutrophil, monocyte and platelet counts and correlated most strongly with neutrophil mobilization immediately (r = 0.709, p < 0.01) and 60-min after vigorous exercise (r = 0.687, p < 0.01). Leukocyte kinetics can be assessed using fingertip blood sampling in exercise settings. Exercise-induced amplification of oxidative burst is detectable with a point-of-care test, but results are strongly influenced by neutrophil counts, which may not be routinely quantified.
Topics: Cross-Over Studies; Exercise; Exercise Test; Female; Humans; Leukocytes; Male; Mitogens; Neutrophils; Reactive Oxygen Species; Respiratory Burst; Young Adult
PubMed: 34496147
DOI: 10.14814/phy2.15010 -
BMC Psychiatry Mar 2023Based on its objective characteristics, laboratory markers have always been the research direction of clinical diagnosis and assessment of mental disorders including...
BACKGROUND
Based on its objective characteristics, laboratory markers have always been the research direction of clinical diagnosis and assessment of mental disorders including Alzheimer's disease.
METHODS
MTT Colorimetric Assay, ELISA, and quantitative PCR were used to investigate the responsiveness of peripheral blood mononuclear cells (PBMCs) to mitogen Lipopolysaccharides (LPS) and Phytohemagglutinin (PHA), PBMCs genomic methylation and hydroxymethylation levels, nuclear DNA and mitochondrial DNA damage, respiratory chain enzyme activities, and circulating cell-free mitochondrial DNA levels were detected in 90 patients with Alzheimer's disease.
RESULTS
In the Alzheimer's disease group, LPS stimulated PBMCs viability, TNF-α secretion, PHA stimulated IL-10 secretion, genomic DNA methylation levels, circulating cell-free mitochondrial DNA copies, citrate synthase activity were reduced compared to the control; while the LPS stimulated PBMCs IL-1α secretion, PHA stimulated IL-1α and IFN-γ secretion, plasma IL-6 and TNF-α, mitochondrial DNA damages were increased compared to the control.
CONCLUSIONS
The reactivity of peripheral blood mononuclear cells to mitogens, mitochondrial DNA integrity characteristics, and cell-free mitochondrial DNA copies may be used as candidate laboratory biomarkers to help clinical management of Alzheimer's disease.
Topics: Humans; Mitogens; Lipopolysaccharides; Leukocytes, Mononuclear; Tumor Necrosis Factor-alpha; Cytokines; DNA, Mitochondrial; Alzheimer Disease; Phytohemagglutinins
PubMed: 36890488
DOI: 10.1186/s12888-023-04634-x -
Cellular and Molecular Gastroenterology... 2021Serotonin signaling is ubiquitous in the gastrointestinal (GI) system, where it acts as a neurotransmitter in the enteric nervous system (ENS) and influences intestinal... (Review)
Review
Serotonin signaling is ubiquitous in the gastrointestinal (GI) system, where it acts as a neurotransmitter in the enteric nervous system (ENS) and influences intestinal motility and inflammation. Since its discovery, serotonin has been linked to cellular proliferation in several types of tissues, including vascular smooth muscle, neurons, and hepatocytes. Activation of serotonin receptors on distinct cell types has been shown to induce well-known intracellular proliferation pathways. In the GI tract, potentiation of serotonin signaling results in enhanced intestinal epithelial proliferation, and decreased injury from intestinal inflammation. Furthermore, activation of the type 4 serotonin receptor on enteric neurons leads to neurogenesis and neuroprotection in the setting of intestinal injury. It is not surprising that the mitogenic properties of serotonin are pronounced within the GI tract, where enterochromaffin cells in the intestinal epithelium produce 90% of the body's serotonin; however, these proliferative effects are attributed to increased serotonin signaling within the ENS compartment as opposed to the intestinal mucosa, which are functionally and chemically separate by virtue of the distinct tryptophan hydroxylase enzyme isoforms involved in serotonin synthesis. The exact mechanism by which serotonergic neurons in the ENS lead to intestinal proliferation are not known, but the activation of muscarinic receptors on intestinal crypt cells indicate that cholinergic signaling is essential to this signaling pathway. Further understanding of serotonin's role in mucosal and enteric nervous system mitogenesis may aid in harnessing serotonin signaling for therapeutic benefit in many GI diseases, including inflammatory bowel disease, malabsorptive conditions, and cancer.
Topics: Animals; Cell Proliferation; Cell Survival; Gastrointestinal Motility; Gastrointestinal Tract; Humans; Mitogens; Receptors, Serotonin; Serotonin; Signal Transduction
PubMed: 34022423
DOI: 10.1016/j.jcmgh.2021.05.008 -
Neuro-oncology Oct 2023Chromosome instability (CIN) with recurrent copy number alterations is a feature of many solid tumors, including glioblastoma (GBM), yet the genes that regulate cell...
BACKGROUND
Chromosome instability (CIN) with recurrent copy number alterations is a feature of many solid tumors, including glioblastoma (GBM), yet the genes that regulate cell division are rarely mutated in cancers. Here, we show that the brain-abundant mitogen, platelet-derived growth factor-A (PDGFA) fails to induce the expression of kinetochore and spindle assembly checkpoint genes leading to defective mitosis in neural progenitor cells (NPCs).
METHODS
Using a recently reported in vitro model of the initiation of high-grade gliomas from murine NPCs, we investigated the immediate effects of PDGFA exposure on the nuclear and mitotic phenotypes and patterns of gene and protein expression in NPCs, a putative GBM cell of origin.
RESULTS
NPCs divided abnormally in defined media containing PDGFA with P53-dependent effects. In wild-type cells, defective mitosis was associated with P53 activation and cell death, but in some null cells, defective mitosis was tolerated. Surviving cells had unstable genomes and proliferated in the presence of PDGFA accumulating random and clonal chromosomal rearrangements. The outcome of this process was a population of tumorigenic NPCs with recurrent gains and losses of chromosomal regions that were syntenic to those recurrently gained and lost in human GBM. By stimulating proliferation without setting the stage for successful mitosis, PDGFA-transformed NPCs lacking P53 function.
CONCLUSIONS
Our work describes a mechanism of transformation of NPCs by a brain-associated mitogen, raising the possibility that the unique genomic architecture of GBM is an adaptation to defective mitosis that ensures the survival of affected cells.
Topics: Humans; Animals; Mice; Mitogens; Tumor Suppressor Protein p53; Mitosis; Neural Stem Cells; Glioblastoma
PubMed: 37186014
DOI: 10.1093/neuonc/noad082