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Life Sciences Jul 1983Mood states and immunity may be related. To investigate the immune status of patients with primary depressive illness, we compared in-vitro lymphocytic responses to... (Comparative Study)
Comparative Study
Mood states and immunity may be related. To investigate the immune status of patients with primary depressive illness, we compared in-vitro lymphocytic responses to three different mitogens in 26 drug-free depressed patients and 20 normal controls of comparable age and sex. We observed a generalized and marked decrease in the lymphocyte mitogenic activity among the depressive group. This defect in lymphocyte function may be indicative of an impairment in cell-mediated immunity in patients with primary depressive illness.
Topics: Adult; Aged; Cells, Cultured; Depressive Disorder; Dose-Response Relationship, Immunologic; Female; Humans; Immunity, Cellular; Lymphocytes; Male; Middle Aged; Mitogens
PubMed: 6865657
DOI: 10.1016/0024-3205(83)90382-x -
Science (New York, N.Y.) Jun 2020Multicellular organisms use mitogens to regulate cell proliferation, but how fluctuating mitogenic signals are converted into proliferation-quiescence decisions is...
Multicellular organisms use mitogens to regulate cell proliferation, but how fluctuating mitogenic signals are converted into proliferation-quiescence decisions is poorly understood. In this work, we combined live-cell imaging with temporally controlled perturbations to determine the time scale and mechanisms underlying this system in human cells. Contrary to the textbook model that cells sense mitogen availability only in the G cell cycle phase, we find that mitogenic signaling is temporally integrated throughout the entire mother cell cycle and that even a 1-hour lapse in mitogen signaling can influence cell proliferation more than 12 hours later. Protein translation rates serve as the integrator that proportionally converts mitogen history into corresponding levels of cyclin D in the G phase of the mother cell, which controls the proliferation-quiescence decision in daughter cells and thereby couples protein production with cell proliferation.
Topics: Cell Proliferation; Cyclin D; G1 Phase; G2 Phase; Humans; Mitogen-Activated Protein Kinase Kinases; Mitogens; Protein Biosynthesis; Signal Transduction; Stem Cells
PubMed: 32241885
DOI: 10.1126/science.aay8241 -
EMBO Molecular Medicine Jan 2022In the course of our studies aiming to discover vascular bed-specific endothelial cell (EC) mitogens, we identified leukemia inhibitory factor (LIF) as a mitogen for...
In the course of our studies aiming to discover vascular bed-specific endothelial cell (EC) mitogens, we identified leukemia inhibitory factor (LIF) as a mitogen for bovine choroidal EC (BCE), although LIF has been mainly characterized as an EC growth inhibitor and an anti-angiogenic molecule. LIF stimulated growth of BCE while it inhibited, as previously reported, bovine aortic EC (BAE) growth. The JAK-STAT3 pathway mediated LIF actions in both BCE and BAE cells, but a caspase-independent proapoptotic signal mediated by cathepsins was triggered in BAE but not in BCE. LIF administration directly promoted activation of STAT3 and increased blood vessel density in mouse eyes. LIF also had protective effects on the choriocapillaris in a model of oxidative retinal injury. Analysis of available single-cell transcriptomic datasets shows strong expression of the specific LIF receptor in mouse and human choroidal EC. Our data suggest that LIF administration may be an innovative approach to prevent atrophy associated with AMD, through protection of the choriocapillaris.
Topics: Animals; Choroid; Endothelial Cells; Geographic Atrophy; Janus Kinases; Leukemia Inhibitory Factor; Mice; Mitogens; STAT3 Transcription Factor
PubMed: 34779136
DOI: 10.15252/emmm.202114511 -
PloS One Jan 2011The development of different brain regions involves the coordinated control of proliferation and cell fate specification along and across the neuraxis. Here, we identify...
The development of different brain regions involves the coordinated control of proliferation and cell fate specification along and across the neuraxis. Here, we identify Plxdc2 as a novel regulator of these processes, using in ovo electroporation and in vitro cultures of mammalian cells. Plxdc2 is a type I transmembrane protein with some homology to nidogen and to plexins. It is expressed in a highly discrete and dynamic pattern in the developing nervous system, with prominent expression in various patterning centres. In the chick neural tube, where Plxdc2 expression parallels that seen in the mouse, misexpression of Plxdc2 increases proliferation and alters patterns of neurogenesis, resulting in neural tube thickening at early stages. Expression of the Plxdc2 extracellular domain alone, which can be cleaved and shed in vivo, is sufficient for this activity, demonstrating a cell non-autonomous function. Induction of proliferation is also observed in cultured embryonic neuroepithelial cells (ENCs) derived from E9.5 mouse neural tube, which express a Plxdc2-binding activity. These experiments uncover a direct molecular activity of Plxdc2 in the control of proliferation, of relevance in understanding the role of this protein in various cancers, where its expression has been shown to be altered. They also implicate Plxdc2 as a novel component of the network of signalling molecules known to coordinate proliferation and differentiation in the developing nervous system.
Topics: Animals; Avian Proteins; Cell Differentiation; Cell Proliferation; Chick Embryo; Mitogens; Neural Stem Cells; Neural Tube; Neurogenesis; Receptors, Cell Surface
PubMed: 21283688
DOI: 10.1371/journal.pone.0014565 -
The Journal of Biological Chemistry May 1997The regulation of protein synthesis was studied in KRC-7 cells (rat hepatoma) grown in complete medium, during serum starvation, and mitogen activation. Upon serum...
The regulation of protein synthesis was studied in KRC-7 cells (rat hepatoma) grown in complete medium, during serum starvation, and mitogen activation. Upon serum starvation, the cells lost almost completely p67 mRNA, p67 protein, and protein synthesis activity. After phorbol 12-myristate 13-acetate addition, the same serum-starved cells regained p67 mRNA, p67 protein, and protein synthesis activity. Also, the extracts from the serum-starved cells phosphorylated the eukaryotic initiation factor-2 (eIF-2) alpha-subunit. This eIF-2 alpha-subunit phosphorylation was not observed when the extracts from either the cells grown in complete medium or mitogen-activated cells were used (Gupta, S., Wu, S., Chatterjee, N., Ilan, J., Ilan, J., Osterman, J. C., and Gupta, N. K. (1995) Gene Expr. 5, 113-122). We now report the following. 1) The eIF-2 kinase activity was the same in the cells grown in complete medium, after serum starvation, and subsequent mitogen stimulation. However, the eIF-2 kinase in the cells grown in complete medium and also after mitogen activation of the serum-starved cells cannot phosphorylate eIF-2 alpha-subunit as these cells contain p67. After removal of endogenous p67 by p67 antibodies, the extracts from all these cells similarly phosphorylated exogenously added eIF-2. 2) None of the cell extracts showed p67 deglycosylase activity. 3) The p67 mRNA was synthesized in serum-starved cells by expression of a p67 cDNA. The appearance of p67 mRNA in the serum-starved cells was accompanied by the appearance of p67 protein. Also, the rates of protein synthesis in the serum-starved cells were restored nearly to the level observed in the confluent cells. The expression of p67 cDNA also significantly increased protein synthesis rates in the cells grown in complete medium and in mitogen-activated cells. These results show that the loss of protein synthesis activity in serum-starved cells was due to loss of p67 mRNA. The expressed p67 mRNA was stable in serum-starved cells. These results, therefore, suggest that the loss of p67 mRNA in serum-starved cells is due to loss of p67 transcription. The p67 transcription regulates translation.
Topics: Aminopeptidases; Animals; Blotting, Northern; Eukaryotic Initiation Factor-2; Glycoproteins; Liver Neoplasms, Experimental; Mitogens; Phosphorylation; Protein Biosynthesis; Rats; Transcription, Genetic
PubMed: 9139727
DOI: 10.1074/jbc.272.19.12699 -
Cell Mar 1997
Review
Topics: Animals; Binding, Competitive; Glycoproteins; Intracellular Signaling Peptides and Proteins; Ligands; Mitogens; Proteins; Proto-Oncogene Proteins; Wnt Proteins; Xenopus; Zebrafish Proteins
PubMed: 9118212
DOI: 10.1016/s0092-8674(00)81915-7 -
American Journal of Reproductive... Jan 2023Amniochorion senescence generates mechanistic signals to initiate parturition. Activation of p38 mitogen-activated kinase (MAPK) in fetal amnion cells is a key mediator...
PROBLEM
Amniochorion senescence generates mechanistic signals to initiate parturition. Activation of p38 mitogen-activated kinase (MAPK) in fetal amnion cells is a key mediator of senescence as well as epithelial-mesenchymal transition (EMT) of amnion cells. However, the impact of p38 MAPK in chorion trophoblast cells (CTCs) is unclear. We tested if eliminating p38 will reduce oxidative stress (OS) induced cell fates like cellular senescence, EMT, and inflammation induced by these processes in CTCs.
METHODS
p38MAPK in CTCs was silenced using CRISPR/Cas9. OS was evoked by cigarette smoke extract (CSE) exposure. EMT was evoked by transforming growth factor (TGF)-ß treatment. Cell cycle, senescence, EMT, and inflammation were analyzed.
RESULTS
CSE-induced changes in the cell cycle were not seen in p38KO CTCs compared to WT cells. OS induced by CSE evoked senescence and senescence-associated secretory phenotype (SASP as indicated by IL-6 and IL-8 increase) in WT but not in p38MAPK KO CTCs. No changes were noted in HLA-G expression regardless of the status of p38MAPK. Neither CSE nor TGF-ß evoked EMT in either WT or p38 KO CTCs.
CONCLUSION
Senescence and senescence-associated inflammation in human fetal CTCs are mediated by p38MAPK. Compared to amnion epithelial cells, CTCs are resistant to EMT. This refractoriness may help them to maintain the barrier functions at the choriodecidual interface.
Topics: Female; Humans; Mitogens; Trophoblasts; Epithelial Cells; Cellular Senescence; Amnion; p38 Mitogen-Activated Protein Kinases; Inflammation
PubMed: 36334089
DOI: 10.1111/aji.13648 -
Proceedings of the National Academy of... Mar 2018Human cells that suffer mild DNA damage can enter a reversible state of growth arrest known as quiescence. This decision to temporarily exit the cell cycle is essential...
Human cells that suffer mild DNA damage can enter a reversible state of growth arrest known as quiescence. This decision to temporarily exit the cell cycle is essential to prevent the propagation of mutations, and most cancer cells harbor defects in the underlying control system. Here we present a mechanistic mathematical model to study the proliferation-quiescence decision in nontransformed human cells. We show that two bistable switches, the restriction point (RP) and the G1/S transition, mediate this decision by integrating DNA damage and mitogen signals. In particular, our data suggest that the cyclin-dependent kinase inhibitor p21 (Cip1/Waf1), which is expressed in response to DNA damage, promotes quiescence by blocking positive feedback loops that facilitate G1 progression downstream of serum stimulation. Intriguingly, cells exploit bistability in the RP to convert graded p21 and mitogen signals into an all-or-nothing cell-cycle response. The same mechanism creates a window of opportunity where G1 cells that have passed the RP can revert to quiescence if exposed to DNA damage. We present experimental evidence that cells gradually lose this ability to revert to quiescence as they progress through G1 and that the onset of rapid p21 degradation at the G1/S transition prevents this response altogether, insulating S phase from mild, endogenous DNA damage. Thus, two bistable switches conspire in the early cell cycle to provide both sensitivity and robustness to external stimuli.
Topics: Cell Cycle; Cell Proliferation; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21; DNA Damage; Gene Knockout Techniques; Humans; Mitogens; Models, Biological; Single-Cell Analysis
PubMed: 29463760
DOI: 10.1073/pnas.1715345115 -
Frontiers in Endocrinology 2022The mechanisms by which insulin activates the insulin receptor to promote metabolic processes and cellular growth are still not clear. Significant advances have been...
The mechanisms by which insulin activates the insulin receptor to promote metabolic processes and cellular growth are still not clear. Significant advances have been gained from recent structural studies in understanding how insulin binds to its receptor. However, the way in which specific interactions lead to either metabolic or mitogenic signalling remains unknown. Currently there are only a few examples of insulin receptor agonists that have biased signalling properties. Here we use novel insulin analogues that differ only in the chemical composition at the A6-A11 bond, as it has been changed to a rigid, non-reducible C=C linkage (dicarba bond), to reveal mechanisms underlying signaling bias. We show that introduction of an A6-A11 dicarba bond into either native insulin or the basal/long acting insulin glargine results in biased signalling analogues with low mitogenic potency. This can be attributed to reduced insulin receptor activation that prevents effective receptor internalization and mitogenic signalling. Insight gained into the receptor interactions affected by insertion of an A6-A11 dicarba bond will ultimately assist in the development of new insulin analogues for the treatment of diabetes that confer low mitogenic activity and therefore pose minimal risk of promoting cancer with long term use.
Topics: Disulfides; Insulin; Intercellular Signaling Peptides and Proteins; Mitogens; Receptor, IGF Type 1; Receptor, Insulin
PubMed: 35832429
DOI: 10.3389/fendo.2022.907864 -
Developmental Dynamics : An Official... May 2011Sonic hedgehog (Shh) controls the number and type of digits formed. Using a conditional genetic approach for timed removal of Shh, we previously proposed a biphasic...
Sonic hedgehog (Shh) controls the number and type of digits formed. Using a conditional genetic approach for timed removal of Shh, we previously proposed a biphasic model of Shh function: a transient patterning phase, during which digit progenitors are specified, and an extended proliferative phase, during which expansion of progenitor pools enables digit formation. Other models favor a close integration of digit patterning and expansion, with sequential promotion to more posterior identity over time, apparently supported by some mutants with selective posterior digit loss. To further test these models, we analyzed the dynamics of Shh activity in several oligodactylous mutants with different types of digit loss. The profile of Shh activity and phenotypic outcome in these mutants supports a biphasic over an integrated temporal model. Eomesodermin expression, as an independent marker of posterior digit identity, confirmed that proper digit 4 specification requires only the transient phase of Shh activity.
Topics: Animals; Body Patterning; Extremities; Gene Expression Regulation, Developmental; Hedgehog Proteins; In Situ Hybridization; Limb Buds; Mice; Mice, Mutant Strains; Mitogens
PubMed: 21509901
DOI: 10.1002/dvdy.22637