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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 -
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 -
The Journal of Biological Chemistry Oct 1998In our present studies utilizing a well characterized proximal tubule cell line, LLCPKcl4, we determined that all four EET regioisomers (5,6-EET, 8,9-EET, 11,12-EET, and...
In our present studies utilizing a well characterized proximal tubule cell line, LLCPKcl4, we determined that all four EET regioisomers (5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET) stimulated [3H]thymidine incorporation, with 14,15-EET being the most potent. In contrast, no mitogenic effects were seen with arachidonic acid, other cP450 arachidonate metabolites (12R-hydroxyeicosatetraenoic acid (12R-HETE), 14,15-dihydroxyeicosatrienoic acid (14,15-DHET), or 20-HETE), or lipoxygenase metabolites (5S-HETE, leukotriene B4, or lipoxin A4). We found that their metabolically more stable sulfonimide (SI) analogs (11,12-EET-SI and 14,15-EET-SI) were also potent mitogens. In addition 14,15-EET-SI also increased cell proliferation as well as expression of both c-fos and egr-1 mRNA. The protein kinase C and A inhibitors, H-7 and H-8, or the cyclooxygenase inhibitor, indomethacin, had no effect upon 14, 15-EET-induced [3H]thymidine incorporation, but the selective tyrosine kinase inhibitor, genistein, significantly inhibited it. Immunoprecipitation and immunoblotting demonstrated increased tyrosine phosphorylation of PI3-kinase and epidermal growth factor receptor (EGFR) within 1 min of EET administration. EETs also stimulated association of PI3-kinase with EGFR. PI3-kinase inhibitors, wortmannin and LY 294002, markedly inhibited 14, 15-EET-SI-stimulated [3H]thymidine incorporation. In addition, 14, 15-EET-SI administration stimulated tyrosine phosphorylation of src homologous and collagen-like protein (SHC) and association of SHC with both growth factor receptor-binding protein (GRB2) and EGFR. Mitogen-activated protein kinase was also activated within 5 min. Pretreatment of the cells with the mitogen-activated protein kinase kinase inhibitor, PD98059, inhibited the 14,15-EET-SI-stimulated [3H]thymidine incorporation. Moreover, immunoblotting indicated that 14,15-EET stimulated tyrosine phosphorylation of the specific pp60(c-src) substrate p120 and c-Src association with EGFR. 14, 15-EET increased src kinase activity within 1 min. Our data indicate that EETs are potent mitogens for renal epithelial cells, and the mitogenic effects of the EETs are mediated, at least in part, by the activation of Src kinase and initiation of a tyrosine kinase phosphorylation cascade.
Topics: 8,11,14-Eicosatrienoic Acid; Adaptor Proteins, Signal Transducing; Animals; Blotting, Western; Cell Line; Enzyme Activation; Epithelial Cells; GRB2 Adaptor Protein; Genes, Immediate-Early; Kidney; Mitogens; Phosphorylation; Protein Binding; Proteins; Swine; Transcription, Genetic; Tyrosine; src-Family Kinases
PubMed: 9786938
DOI: 10.1074/jbc.273.44.29254 -
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 -
IUBMB Life Jul 2001The potential for carotenoids to modulate tumor growth is currently under investigation. Although epidemiological studies evidence that a high intake of vegetables, rich... (Review)
Review
The potential for carotenoids to modulate tumor growth is currently under investigation. Although epidemiological studies evidence that a high intake of vegetables, rich in carotenoids, decreases cancer incidence and mortality, clinical trials demonstrate that supplementation of beta-carotene to chronic smokers or to asbestos workers increases the risk for lung cancer. These contradictory findings have renewed interest in elucidating the mechanism of action of carotenoids in biological systems. In this review, we show evidence for mitogenic and apoptotic effects of carotenoids and we support the hypothesis that these molecules may act as anticarcinogens or as procarcinogens through a redox mechanism. In particular, we report demonstrations for the anti-oxidant or pro-oxidant effects of carotenoids in vitro and in vivo, focusing our attention on the relationship existing between cell growth and redox status.
Topics: Animals; Apoptosis; Carotenoids; Cell Differentiation; Cell Division; Humans; Mitogens; Oxidation-Reduction; Signal Transduction
PubMed: 11795599
DOI: 10.1080/15216540252774810 -
Cell Reports Aug 2017The recent discovery of metabolic roles for fibroblast growth factor 1 (FGF1) in glucose homeostasis has expanded the functions of this classically known mitogen. To...
The recent discovery of metabolic roles for fibroblast growth factor 1 (FGF1) in glucose homeostasis has expanded the functions of this classically known mitogen. To dissect the molecular basis for this functional pleiotropy, we engineered an FGF1 partial agonist carrying triple mutations (FGF1) that diminished its ability to induce heparan sulfate (HS)-assisted FGF receptor (FGFR) dimerization and activation. FGF1 exhibited a severely reduced proliferative potential, while preserving the full metabolic activity of wild-type FGF1 in vitro and in vivo. Hence, suboptimal FGFR activation by a weak FGF1-FGFR dimer is sufficient to evoke a metabolic response, whereas full FGFR activation by stable and sustained dimerization is required to elicit a mitogenic response. In addition to providing a physical basis for the diverse activities of FGF1, our findings will impact ongoing drug discoveries targeting FGF1 and related FGFs for the treatment of a variety of human diseases.
Topics: 3T3-L1 Cells; Animals; Binding Sites; Cell Line, Tumor; Cloning, Molecular; Escherichia coli; Fibroblast Growth Factor 1; Gene Expression; Hepatocytes; Humans; Mice; Mice, Inbred C57BL; Mitogens; Models, Molecular; NIH 3T3 Cells; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Protein Multimerization; Protein Stability; Rats; Receptors, Fibroblast Growth Factor; Recombinant Proteins
PubMed: 28813681
DOI: 10.1016/j.celrep.2017.06.063 -
Toxicological Sciences : An Official... May 2017Low molecular weight polycyclic aromatic hydrocarbons (LMW PAHs; < 206.3 g/mol) are prevalent and ubiquitous environmental contaminants, presenting a human health...
Low molecular weight polycyclic aromatic hydrocarbons (LMW PAHs; < 206.3 g/mol) are prevalent and ubiquitous environmental contaminants, presenting a human health concern, and have not been as thoroughly studied as the high MW PAHs. LMW PAHs exert their pulmonary effects, in part, through P38-dependent and -independent mechanisms involving cell-cell communication and the production of pro-inflammatory mediators known to contribute to lung disease. Specifically, we determined the effects of two representative LMW PAHs, 1-methylanthracene (1-MeA) and fluoranthene (Flthn), individually and as a binary PAH mixture on the dysregulation of gap junctional intercellular communication (GJIC) and connexin 43 (Cx43), activation of mitogen activated protein kinases (MAPK), and induction of inflammatory mediators in a mouse non-tumorigenic alveolar type II cell line (C10). Both 1-MeA, Flthn, and the binary PAH mixture of 1-MeA and Flthn dysregulated GJIC in a dose and time-dependent manner, reduced Cx43 protein, and activated the following MAPKs: P38, ERK1/2, and JNK. Inhibition of P38 MAPK prevented PAH-induced dysregulation of GJIC, whereas inhibiting ERK and JNK did not prevent these PAHs from dysregulating GJIC indicating a P38-dependent mechanism. A toxicogenomic approach revealed significant P38-dependent and -independent pathways involved in inflammation, steroid synthesis, metabolism, and oxidative responses. Genes in these pathways were significantly altered by the binary PAH mixture when compared with 1-MeA and Flthn alone suggesting interactive effects. Exposure to the binary PAH mixture induced the production and release of cytokines and metalloproteinases from the C10 cells. Our findings with a binary mixture of PAHs suggest that combinations of LMW PAHs may elicit synergistic or additive inflammatory responses which warrant further investigation and confirmation.
Topics: Animals; Cell Communication; Cell Line; Connexin 43; Dose-Response Relationship, Drug; Enzyme Activation; Epithelial Cells; Gap Junctions; Inflammation; Lung; Mice; Mitogen-Activated Protein Kinases; Mitogens; Polycyclic Aromatic Hydrocarbons; Signal Transduction; Tobacco Smoke Pollution; Transcriptome
PubMed: 28329830
DOI: 10.1093/toxsci/kfx027 -
Effects on coagulation factor production following primary hepatomitogen-induced direct hyperplasia.World Journal of Gastroenterology Nov 2009To investigate the molecular mechanisms involved in coagulation factor expression and/or function during direct hyperplasia (DH)-mediated liver regeneration.
AIM
To investigate the molecular mechanisms involved in coagulation factor expression and/or function during direct hyperplasia (DH)-mediated liver regeneration.
METHODS
Direct hyperplasia-mediated liver regeneration was induced in female C57BL/6 mice by administering 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), a representative hepatomitogen. Mice were weighed and sacrificed at various time points [Day 0 (D0: prior to injection), 3 h, D1, D2, D3, and D10] after TCPOBOP administration to obtain liver and blood samples. Using the RNA samples extracted from the liver, a comprehensive analysis was performed on the hepatic gene expression profiling of coagulation-related factors by real-time RT-PCR (fibrinogen, prothrombin, factors V, VII, VIII, IX, X, XI, XII, XIIIbeta, plasminogen, antithrombin, protein C, protein S, ADAMTS13, and VWF). The corresponding plasma levels of coagulation factors (fibrinogen, prothrombin, factors V, VII, VIII, IX, X, XI, XII, XIII, and VWF) were also analyzed and compared with their mRNA levels.
RESULTS
Gavage administration of TCPOBOP (3 mg/kg body weight) resulted in a marked and gradual increase in the weight of the mouse livers relative to the total body weight to 220% by D10 relative to the D0 (control) ratios. At the peak of liver regeneration (D1 and D2), the gene expression levels for most of the coagulation-related factors (fibrinogen, prothrombin, factors V, VII, VIII, IX, XI, XII, XIIIbeta, plasminogen, antithrombin, protein C, ADAMTS13, VWF) were found to be down-regulated in a time-dependent manner, and gradually recovered by D10 to the basal levels. Only mRNA levels of factor X and protein S failed to show any decrease during the regenerative phase. As for the plasma levels, 5 clotting factors (prothrombin, factors VIII, IX, XI, and XII) demonstrated a significant decrease (P<0.05) during the regeneration phase compared with D0. Among these 5 factors, factor IX and factor XI showed the most dramatic decline in their activities by about 50% at D2 compared to the basal levels, and these reductions in plasma activity for both factors were consistent with our RT-PCR findings. In contrast, the plasma activities of the other coagulation factors (fibrinogen, factors V, VII, XIII, and VWF) were not significantly reduced, despite the reduction in the liver mRNA levels. Unlike the other factors, FX showed a temporal increase in its plasma activity, with significant increases (P<0.05) detected at D1.
CONCLUSION
Investigating the coagulation cascade protein profiles during liver regeneration by DH may help to better understand the basic biology of the liver under normal and pathological conditions.
Topics: Animals; Blood Coagulation Factors; Blood Coagulation Tests; Disease Models, Animal; Female; Gene Expression Profiling; Hyperplasia; Liver; Liver Regeneration; Mice; Mice, Inbred C57BL; Mitogens; Pyridines; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 19908339
DOI: 10.3748/wjg.15.5307 -
The Journal of Infection May 2019Superantigens are ubiquitous within the Streptococcus pyogenes genome, which suggests that superantigen-mediated T-cell activation provides a significant selective...
Superantigens are ubiquitous within the Streptococcus pyogenes genome, which suggests that superantigen-mediated T-cell activation provides a significant selective advantage. S. pyogenes can carry a variable complement of the 11 known superantigens. We have identified two novel S. pyogenes superantigens, denoted speQ and speR, adjacent to each other in the core-chromosome of isolates belonging to eleven different emm-types. Although distinct from other superantigens, speQ and speR were most closely related to speK and speJ, respectively. Recombinant SPEQ and SPER were mitogenic towards human peripheral blood mononuclear cells at ng/ml concentrations, and SPER was found to be more mitogenic than SPEQ.
Topics: Antigens, Bacterial; Cell Proliferation; Cells, Cultured; Chromosomes, Bacterial; Genes, Bacterial; Humans; Leukocytes, Mononuclear; Mitogens; Sequence Homology; Streptococcus pyogenes; Superantigens
PubMed: 30796950
DOI: 10.1016/j.jinf.2019.02.005 -
Cancer Letters Dec 2012The epithelial to mesenchymal transition (EMT) is a process by which differentiated epithelial cells transition to a mesenchymal phenotype. EMT enables the escape of...
The epithelial to mesenchymal transition (EMT) is a process by which differentiated epithelial cells transition to a mesenchymal phenotype. EMT enables the escape of epithelial cells from the rigid structural constraints of the tissue architecture to a phenotype more amenable to cell migration and, therefore, invasion and metastasis. We characterized an in vivo model of EMT and discovered that marked changes in mitogenic signaling occurred during this process. DNA microarray analysis revealed that the expression of a number of genes varied significantly between post-EMT and pre-EMT breast cancer cells. Post-EMT cancer cells upregulated mRNA encoding c-Met and the PDGF and LPA receptors, and acquired increased responsiveness to HGF, PDGF, and LPA. This rendered the post-EMT cells responsive to the growth inhibitory effects of HGF, PDGF, and LPA receptor inhibitors/antagonists. Furthermore, post-EMT cells exhibited decreased basal Raf and Erk phosphorylation, and in comparison to pre-EMT cells, their proliferation was poorly inhibited by a MEK inhibitor. These studies suggest that therapies need to be designed to target both pre-EMT and post-EMT cancer cells and that signaling changes in post-EMT cells may allow them to take advantage of paracrine signaling from the stroma in vivo.
Topics: Animals; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Humans; Mice; Mitogens; Models, Biological; Oligonucleotide Array Sequence Analysis
PubMed: 22906417
DOI: 10.1016/j.canlet.2012.08.013