Diverse FSH and testosterone signaling pathways in the Sertoli cell.

FSH and testosterone exert different regulatory effects on the seminiferous epithelium; they act through multiple and complex signaling routes to direct the development of the germ cells into mature spermatozoa. In addition to their well-known pathways of action, both hormones have recently been recognized to have new signaling routes that are linked to the Ca(2+) ion, including, among others, the regulation of cell proliferation by FSH and the regulation of cell migration by testosterone.     

Signal transduction pathways in mast cell granule-mediated endothelial cell activation

BACKGROUND: We have previously shown that incubation of human endothelial cells with mast cell granules results in potentiation of lipopolysaccharide-induced production of interleukin-6 and interleukin-8. AIMS: The objective of the present study was to identify candidate molecules and signal transduction pathways involved in the synergy between mast cell granules and lipopolysaccharide on endothelial cell activation. METHODS: Human umbilical vein endothelial cells were incubated with rat mast cell granules in the presence and absence of lipopolysaccharide, and IL-6 production was quantified. The status of c-Jun amino-terminal kinase and extracellular signal-regulated kinase 1/2 activation, nuclear factor-kappaB translocation and intracellular calcium levels were determined to identify the mechanism of synergy between mast cell granules and lipopolysaccaride. RESULTS: Mast cell granules induced low levels of interleukin-6 production by endothelial cells, and this effect was markedly enhanced by lipopolysaccharide. The results revealed that both serine proteases and histamine present in mast cell granules were involved in this activation process. Mast cell granules increased intracellular calcium, and activated c-Jun amino-terminal kinase and extracellular signal-regulated kinase 1/2. The combination of lipopolysaccharide and mast cell granules prolonged c-Jun amino-terminal kinase activity beyond the duration of induction by either stimulant alone and was entirely due to active proteases. However, both proteases and histamine contributed to calcium mobilization and extracellular signal-regulated kinase 1/2 activation. The nuclear translocation of nuclear factor-kappaB proteins was of greater magnitude in endothelial cells treated with the combination of mast cell granules and lipopolysaccharide. CONCLUSIONS:Mast cell granule serine proteases and histamine can amplify lipopolysaccharide-induced endothelial cell activation, which involves calcium mobilization, mitogen-activated protein kinase activation and nuclear factor-kappaB translocation.     

Signal transduction pathways involved in mechanical regulation of HB-GAM expression in osteoblastic cells

Protein kinase C (PKC), protein kinase A (PKA), prostaglandin synthesis, and various mitogen-activated protein kinases (MAPKs) have been reported to be activated in bone cells by mechanical loading. We studied the involvement of these signal transduction pathways in the downregulation of HB-GAM expression in osteoblastic cells after cyclic stretching. Specific antagonists and agonists of these signal transduction pathways were added to cells before loading and to non-loaded control cells. Quantitative RT-PCR was used to evaluate gene expression. The data demonstrated that the extracellular signal-regulated kinase (ERK) 1/2 pathway, PKC, PKA, p38, and c-Jun N-terminal kinase MAPK participated in the mechanical downregulation of HB-GAM expression, whereas prostaglandin synthesis did not seem to be involved.     

Signal transduction pathways to apoptosis

Recent work has demonstrated that a number of signalling events, including cytosolic Ca(2+) rises, cAMP accumulation, activation of protein kinase C, activation of protein tyrosine kinases, and production of ceramide, regulate apoptosis in diverse model systems. However, in some cells these signals promote apoptosis, whereas in others they block the response. This review discusses these observations and proposes explanations for how a given set of signal transduction systems might be involved in multiple cellular responses.     

Signal transduction of somatostatin receptors negatively controlling cell proliferation.

Somatostatin acts as an inhibitory peptide of various secretory and proliferative responses. Its effects are mediated by a family of G-protein-coupled receptors (sst1-5) that can couple to diverse signal transduction pathways such as inhibition of adenylate cyclase and guanylate cyclase, modulation of ionic conductance channels, and protein dephosphorylation. The five receptors bind the natural peptide with high affinity but only sst2, sst5 and sst3 bind the short synthetic analogues. Somatostatin negatively regulates the growth of various normal and tumour cells. This effect is mediated indirectly through inhibition of secretion of growth-promoting factors, angiogenesis and modulation of the immune system. Somatostatin can also act directly through sst receptors present on target cells. The five receptors are expressed in various normal and tumour cells, the expression of each receptor being receptor subtype and cell type specific. According to the receptor subtypes, distinct signal transduction pathways are involved in the antiproliferative action of somatostatin. Sst1, 4 and 5 modulate the MAP kinase pathway and induce G1 cell cycle arrest. Sst3 and sst2 promote apoptosis by p53-dependent and -independent mechanisms, respectively.     

Signal transduction pathways of mantle cell lymphoma: a phosphoproteome-based study

Mantle cell lymphoma (MCL) is an incurable hematologic malignancy whose pathogenesis is only partly understood. The aim of the present study was to define a "core phosphoproteome" in MCL cell lines that is representative of primary MCL in order to improve knowledge of the signal transduction pathways involved in its tumorigenesis. We have analyzed phosphorylated proteins in several MCL cell lines by immobilized metal affinity chromatography and separation by 2-D PAGE, followed by RP-HPLC coupled with MS/MS identification. These data were correlated with information on copy number gains obtained by SNP-chip analysis. Several of the proteins identified could be linked to a specific signal transduction pathway, and have been recently recognized as important players in MCL pathogenesis, such as nuclear factor-kappaB (NF-kappaB) and phosphoinositide-3 kinase-mammalian target of rapamycin (PI3K-mTOR). However, our data also implicate a number of novel proteins and pathways in the pathobiology of MCL, one of which is mitochondrial signaling. A second-level analysis identified MAPK1, CK2, CK1, PKCzeta, and PKCepsilon as candidate upstream molecules. Our study provides new insights in MCL pathogenesis and helps to form the basis for testing new target-specific therapeutics.     

Effects of carbachol on rat Sertoli cell proliferation and muscarinic acetylcholine receptors regulation: an in vitro study

The aim of the present work was to study the effect of muscarinic agonist on cell proliferation and muscarinic acetylcholine receptors (mAChRs) regulation in rat Sertoli cells. Primary cultures of Sertoli cells were obtained from 8-day and 15-day old male Wistar rats. In proliferation assays, [methyl-3H]thymidine incorporation in Sertoli cells from 8-day and 15-day old rats reached a plateau after 60 min of carbachol incubation and decreased after 120 min of agonist incubation. Binding studies with [N-Methyl-3H]scopolamine ([3H]NMS) indicated a rapid loss of cell surface mAChRs when Sertoli cells from 15-day old rats were incubated with carbachol at 35 degrees C for 2 min. This effect was temperature-dependent. When the incubation of the cells was prolonged at 35 degrees C or at 4 degrees C, after the agonist had been washed away, 94% of mAChRs were present in the cell surface after 120 min incubation at 35 degrees C. At 4 degrees C, however, a low percentage of mAChRs was detected in the cell surface. In the presence of cycloheximide, the recycling of mAChRs to the cell surface was not changed, suggesting that the appearance of mAChRs on cell surface was not dependent on de novo receptor synthesis. In conclusion, our studies indicate that the activation of mAChRs may play a role in rat Sertoli cell proliferation. These receptors may be under regulation (internalization and recycling) when cells are exposed to muscarinic cholinergic agonist.     

Mitogenic effect of erythropoietin on neonatal rat cardiomyocytes: Signal transduction pathways

The mitogenic effect of recombinant human erythropoietin (rHuEpo) on primary cultures of neonatal rat cardiac myocytes was observed. rHuEpo triggered a dose-dependent increase in myocyte proliferation. The hormone effect over optimally grown control culture 1 day after addition was maximum with 0.5 U/ml and was inhibited with anti-rHuEpo. Inhibitors of enzymatic pathways known to be involved in the cytokines intracellular mechanism such as genistein (tyrosine kinase inhibitor), 2-nitro-4-carboxiphenyl-N,N-diphenylcarbamate (phospholipase C [PLC] inhibitor), and 1-(5-isoquinolinylsufonyl)-2-methyl-piperazine (protein kinase C [PKC] inhibitor) prevented the mitogenic action of rHuEpo. Also the inhibition of Na⁺-K⁺-ATPase activity by ouabain blunted the stimulatory action of rHuEpo on cell proliferation. The mitogenic action of the hormone was correlated with cardiac membrane paranitrophenilphosphatase (pNPPase) and PKC activity, since concentrations of rHuEpo that stimulate DNA synthesis increased pNPPase and PKC activity. Moreover, the enzymatic inhibition of tyrosine kinase, PLC, and PKC attenuated the stimulatory action of rHuEpo upon cardiac pNPPase activity. In this paper we demonstrate a non-hematopoietic action of rHuEpo showing both mitogenic and enzymatic effect upon primary myocyte cell culture and on pNPPase activity of neonatal rat heart. These effects are related to the capacity of rHuEpo to stimulate Na⁺-K⁺-ATPase activity and appear to be secondary to the activation of tyrosine kinase and PKC, indicating that in the rHuEpo mediated mitogenic action on cardiomyocytes involves the activation of the same enzymatic pathways that have been described by other cytokines in different tissues. © 1996 Wiley-Liss, Inc.     

Role of raf isoforms in signal transduction pathways relevant to leukemia cell proliferation

The invited commentary is addressed to the paper of Shelton et al published in this issue of Cell Cycle. The intracellular pathways that control cell growth constitute a complex nexus of signaling interactions that serve to regulate cell proliferation, differentiation and apoptosis. Dysregulation of these processes leads to the loss of control of cell growth that is characteristic of malignancy. Understanding cell signaling is a major challenge for modern biological research. One way to begin to unravel the intricate web of signaling pathways is to investigate the effects of mutant forms of key component proteins. One such protein is the serine/threonine-specific protein kinase, Raf.     

IL-3在造血干细胞增殖分化调控中的信号转导

IL-3又称多克隆集落刺激因子（Multi-CSF）,是造血干细胞增殖分化的正性调节因子。它通过与靶细胞表面的受体结合传递生长、分化信号,调控造血干细胞生存、增殖及向各系血细胞分化、成熟。本文就IL-3在造血干细胞增殖分化调控中的有关信号转导作一综述。     

Signal transduction pathways linking polyamines to apoptosis

Summary. Polyamines are important multifunctional cellular components and are classically considered as mediators of cell growth and division. Recently polyamines have been also implicated in cell death. Now it appears that polyamines are bivalent regulators of cellular functions, promoting proliferation or cell death depending on the cell type and on environmental signals. This review draws a picture about the role of polyamines in signalling pathways related to apoptotic cell death and the proposed molecular targets of these polycations at the level of the apoptotic cascade. Solid evidence indicates that polyamines may affect the mitochondrial and postmitochondrial phases of apoptosis, by modulating cytochrome c release from mitochondria and activation of caspases. Recently, polyamines have been also implicated in the regulation of the premitochondrial phase of apoptosis, during which upstream apoptotic signal transduction pathways are activated. The studies reviewed here suggest that polyamines may participate in loops involving interaction with signal transduction pathways and activation/expression of proteins that may control cell death or cell growth.     

Homeostatic regulation of germinal stem cell proliferation by the GDNF/FSH pathway

Stem cell regulatory mechanisms are difficult to study because self-renewal and production of differentiated progeny, which are both strictly controlled, occur simultaneously in these cells. To focus on the self-renewal mechanism alone, we investigated the behavior of germinal stem cells (GSCs) in progeny-deficient testes with defective GSC differentiation. In these testes, we found that the proliferation of undifferentiated spermatogonia, some of which are GSCs, was accelerated by high concentrations of glial cell line-derived neurotrophic factor (GDNF). Furthermore, we found that follicle-stimulating hormone (FSH) stimulation via homeostatic control was one of the major regulators of GDNF concentration. These results suggest that in mammalian testes, GSC proliferation and population size are regulated homeostatically by the GDNF/FSH pathway.     

Signal transduction and regulation of neurotrophins.

Our understanding of the molecular nature of neurotrophic interactions has been greatly enhanced by the recent isolation and characterization of several new neurotrophic factors and their receptors. Neurotrophic factors have been found to be regulated by neuronal activity in the central nervous system, and may be involved in activity-dependent processes throughout development and maturity.