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Results for “Autocrine Communication”

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At least 271 records · Page 15Linked to original sources
PubMed2004

Inducible production of interferon-gamma in the developing brain causes cerebellar dysplasia with activation of the Sonic hedgehog pathway.

Here we examined the role of interferon (IFN)-gamma in regulating the Sonic hedgehog (Shh) pathway and cerebellar development in bigenic mice with temporal control of IFN-gamma gene expression driven by a tetracycline-controllable promoter. In IFN-gamma-expressing but not age-matched non-IFN-gamma-expressing bigenic or control mice, development of the cerebellum was severely affected with the persistence and extensive proliferation of the external granule neuron layer (EGL) and infiltration with modest numbers of T-lymphocytes. Following induction of IFN-gamma transgene expression, both total and tyrosine-phosphorylated signal transducer and activator of transcription (STAT)1 (the major transcriptional factor for IFN-gamma), phosphorylated STAT3 and STAT5, and expression of a number of IFN-gamma-regulated genes were significantly increased in cerebellum. In the cerebellum from IFN-gamma-expressing but not age-matched non-IFN-gamma-expressing mice, the level of Shh and Gli-1 but not Patched (Ptch) 1 RNA was increased as was the 19-kDa signaling product of the Shh precursor protein. In situ localization studies revealed ectopic expression of the Shh gene by the granule neurons. We conclude that IFN-gamma directly affects the proliferation and fate of EGL neurons in the cerebellum by activating the Shh pathway and stimulating an autocrine growth response by these cells.

Animals↗
PubMed2004

JNK regulates autocrine expression of TGF-beta1.

The c-Jun NH2-terminal kinase (JNK) has been implicated in the function of transforming growth factor beta (TGF-beta). To test the role of JNK, we examined the effect of compound disruption of the murine genes that encode the ubiquitously expressed isoforms of JNK (Jnk1 and Jnk2). We report that JNK-deficient fibroblasts isolated from Jnk1-/- Jnk2-/- mice constitutively express TGF-beta1. Complementation studies demonstrate that JNK is a repressor of Tgf-beta1 gene expression. This mechanism of regulation of TGF-beta1 expression by JNK represents an unexpected form of cross-talk between two important signaling pathways. Together, these data demonstrate that the JNK pathway may contribute to the regulation of autocrine TGF-beta1-mediated biological responses in vivo.

Activin Receptors, Type I↗
PubMed2004

JNK regulates expression and autocrine signaling of TGF-beta1.

TGF-beta1 can induce its own expression by an autoregulatory mechanism. In this issue of Molecular Cell, Ventura et al. (2004) show, using JNK-deficient fibroblasts, that JNK negatively regulates TGF-beta1 gene expression and, consequently, autocrine TGF-beta signaling. The results highlight the contributions of JNK signaling in the control of TGF-beta expression and signaling, and of autocrine TGF-beta signaling in the JNK-regulated changes in cell behavior.

Animals↗
PubMed2005

Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization.

The protein kinase B-RAF is mutated in approximately 7% of human cancers. Most mutations are activating, but, surprisingly, a small number have reduced kinase activity. However, the latter can still stimulate cellular signaling through the MEK-ERK pathway because they activate the related family member C-RAF. We examine the mechanism underlying C-RAF activation by B-RAF. We show that C-RAF is activated in the cytosol in a RAS-independent manner that requires activation segment phosphorylation and binding of 14-3-3 to C-RAF. We show that wild-type B-RAF forms a complex with C-RAF in a RAS-dependent manner, whereas the mutants bind independently of RAS. Importantly, we show that wild-type B-RAF can also activate C-RAF. Our data suggest that B-RAF activates C-RAF through a mechanism involving 14-3-3 mediated heterooligomerization and C-RAF transphosphorylation. Thus, we have identified a B-RAF-C-RAF-MEK-ERK cascade that signals not only in cancer but also in normal cells.

14-3-3 Proteins↗
PubMed2005

Pigment epithelium-derived factor (PEDF) promotes growth of pericytes through autocrine production of platelet-derived growth factor-B.

Microvessels are composed of two types of cells, endothelial cells and pericytes. Pericyte loss or dysfunction participates in various types of disorders, including diabetic retinopathy. Recently, decreased levels of pigment epithelium-derived factor (PEDF) in the eye have been found to predict progression of diabetic retinopathy. However, the effect of PEDF on pericyte growth remains to be unknown. In this study, we investigated whether or how PEDF could stimulate proliferation of cultured retinal pericytes. PEDF stimulated DNA synthesis in pericytes in a dose-dependent manner. PEDF up-regulated pericyte mRNA levels of platelet-derived growth factor-B (PDGF-B). Down-regulation of PDGF-B gene expression by small interfering RNAs completely inhibited the PEDF-induced DNA synthesis in pericytes. Furthermore, PEDF increased protein kinase C (PKC) activity in pericytes and staurosporine, a potent cell-permeable inhibitor of PKC, completely blocked the PDGF-B gene induction and subsequent increase in DNA synthesis in PEDF-exposed pericytes. These results demonstrate that PEDF promotes the growth of cultured pericytes possibly through autocrine production of PDGF-B via PKC activation. Our present study suggests that PEDF could act as a mitogen or survival factor for pericytes, thereby being involved in the maintenance of retinal microvascular homeostasis.

Animals↗
PubMed2004

Serotonin regulates the secretion and autocrine action of a neuropeptide to activate MAPK required for long-term facilitation in Aplysia.

In Aplysia, long-term facilitation (LTF) of sensory neuron synapses requires activation of both protein kinase A (PKA) and mitogen-activated protein kinase (MAPK). We find that 5-HT through activation of PKA regulates secretion of the sensory neuron-specific neuropeptide sensorin, which binds autoreceptors to activate MAPK. Anti-sensorin antibody blocked LTF and MAPK activation produced by 5-HT and LTF produced by medium containing sensorin that was secreted from sensory neurons after 5-HT treatment. A single application of 5-HT followed by a 2 hr incubation with sensorin produced protein synthesis-dependent LTF, growth of new presynaptic varicosities, and activation of MAPK and its translocation into sensory neuron nuclei. Inhibiting PKA during 5-HT applications and inhibiting receptor tyrosine kinase or MAPK during sensorin application blocked both LTF and MAPK activation and translocation. Thus, long-term synaptic plasticity is produced when stimuli activate kinases in a specific sequence by regulating the secretion and autocrine action of a neuropeptide.

Amino Acid Sequence↗
PubMed2004

Glia cell line-derived neurotrophic factor regulates the distribution of acetylcholine receptors in mouse primary skeletal muscle cells.

It was recently reported that glia cell line-derived neurotrophic factor (GDNF) facilitates presynaptic axonal growth and neurotransmitter release at neuromuscular synapses. Little is known, however, whether GDNF can also act on the postsynaptic apparatus and its underlying mechanisms. Using biochemical cold blocking of existing membrane acetylcholine receptors (AchRs) and biotinylation of newly inserted receptors we demonstrate that GDNF increases the insertion of AChRs into the surface membrane of mouse primary cultured muscle cells and that this does not require protein synthesis. Quantitative data from double-label imaging indicate that GDNF induces a quick and substantial increase in AchR insertion as well as lateral movement into AchR aggregates, relative to a weak effect on reducing the loss of receptors from pre-existing AchR aggregates, which in contrast to the effect of PMA. These effects occur in both innervated and un-innervated muscles, and GDNF affects nerve-muscle co-cultures more than it affects muscle-only cultures. Neurturin, another member of GDNF-family ligands has similar effects on AchRs as GDNF but the unrelated growth factor, EGF does not. Studies on protein phosphorylation and specific inhibitors of cell signal transduction indicate that GDNF function is mediated by receptor GFRalpha1 and involves MAPK, cAMP/cAMP responsive element-binding factor and Src kinase activities. GDNF may signal through c-Ret as well as NCAM-140 pathways since both the signaling receptors are expressed in the neuromuscular junction (NMJ). These data suggest that GDNF is an autocrine regulator of NMJ to promote the insertion and stabilization of postsynaptic AchRs. In vivo, GDNF may function as a synaptotrophic modulator for both pre- and postsynaptic differentiation to strengthen the functional and structural connections between nerve and muscle, and contribute to the synaptogenesis and plasticity of neuromuscular synapses.

Animals↗
PubMed2005

Tenascin-C regulates proliferation and migration of cultured astrocytes in a scratch wound assay.

Tenascin-C (TNC), an extracellular matrix glycoprotein, is involved in tissue morphogenesis like embryogenesis, wound healing or tumorigenesis. Astrocytes are known to play major roles in wound healing in the CNS. To elucidate the roles of TNC in wound closure by astrocytes, we have examined the morphological changes of cultured astrocytes in a scratch wound assay and measured the content of soluble TNC released into the medium. We have also localized the expression of TNC mRNA, TNC, glial fibrillary acidic protein (GFAP), vimentin and integrin beta1. After wounding, glial cells rapidly released the largest TNC isoform and proliferated in the border zones. Subsequently, they became polarized with unidirectional processes and finally migrated toward the denuded area. The proliferating border zone cells and pre-migratory cells intensely expressed TNC mRNA, TNC-, vimentin-, GFAP- and integrin beta1-like immunoreactivity, while the migratory cells showed generally reduced expression except the front. Exogenous TNC enhanced cell proliferation and migration, while functional blocking with anti-TNC or anti-integrin beta1 antibody reduced both of them. These results suggest that mechanical injury induces boundary astrocytes to produce and release TNC that promotes cell proliferation and migration via integrin beta1 in an autocrine/paracrine fashion.

Animals↗
PubMed2006

Expression of angiogenic and neurotrophic factors in the progenitor cell niche of adult monkey subventricular zone.

The subventricular zone along the anterior horn (SVZa) of the cerebral lateral ventricle of adult mammals contains multipotent progenitor cells, which supposedly exist in an angiogenic niche. Numerous signals are known to modulate the precursor cell proliferation, migration or differentiation, in rodent models. In contrast, the data on signals regulating the primate SVZa precursors in vivo are scarce. We analyzed the expression at protein level of a panel of angiogenic and/or neurotrophic factors and their receptors in SVZa of adult macaque monkeys, under normal condition or after transient global ischemia which enhances endogenous progenitor cell proliferation. We found that fms-like tyrosine kinase 1 (Flt1), a receptor for vascular endothelial cell growth factor, was expressed by over 30% of the proliferating progenitors, and the number of Flt1-positive precursors was significantly increased by the ischemic insult. Smaller fractions of mitotic progenitors were positive for the neurotrophin receptor tropomyosin-related kinase (Trk) B or the hematopoietic receptor Kit, while immature neurons expressed Flt1 and the neurotrophin receptor TrkA. Further, SVZa astroglia, ependymal cells and blood vessels were positive for distinctive sets of ligands/receptors, which we characterized. The presented data provide a molecular phenotypic analysis of cell types comprising adult monkey SVZa, and suggest that a complex network of angiogenic/neurotrophic signals operating in an autocrine or paracrine manner may regulate SVZa neurogenesis in the adult primate brain.

Angiogenic Proteins↗
PubMed2004

The effect of neurotensin on insulin-induced proliferation of human fibroblasts.

Neurotensin has been shown to influence growth in a number of cancerous and non-cancerous cells and to enhance the proliferative effects of growth factors without itself inducing proliferation. Here we show that neurotensin potentiates the proliferative effects of insulin on IMR90 human fibroblasts in a concentration and neurotensin receptor type 1-dependent manner. This potentiating effect of neurotensin was blocked by inhibitors of phospholipase C and protein kinase C, was accompanied by an increase in the level of soluble inositol phosphates and did not involve an autocrine factor. These results show that neurotensin can enhance insulin-dependent proliferation of human fibroblasts and suggest a possible role for neurotensin in tissue growth and repair.

Autocrine Communication↗
PubMed2005

Insulin-like growth factor (IGF) induced proliferation of human lung fibroblasts is enhanced by neurotensin.

Fibroblasts are key cells in tissue repair and important contributors to the inflammatory response. Insulin-like growth factors (IGFs) have been shown to participate in growth, in immune responses and in tissue repair where they stimulate cell growth. Neurotensin (NT) has been suggested to participate in inflammation and in tissue repair and is an autocrine or paracrine growth factor for several cancer cell types. Here we show that IGF-induced proliferation of fibroblasts is enhanced by NT in a concentration and type 1 NT-receptor dependent manner. This action of NT was blocked by inhibitors of phospholipase C and protein kinase C but not by inhibitors of phosphoinositide-3-kinase. An inhibitor of MEK 1/2 significantly reduced the proliferative effects of the IGFs but NT's ability to enhance IGF-induced proliferation was not effected. The ability of NT to enhance IGF-induced proliferation did not involve an autocrine factor. These results suggest that interactions between NT and the IGFs may contribute to the regulation of fibroblasts in for example, inflamed or injured tissues.

Autocrine Communication↗
PubMed2005

Expression of urocortin 3/stresscopin in human adrenal glands and adrenal tumors.

Urocortin 3 (Ucn 3)/stresscopin (SCP) is a novel peptide of the corticotropin-releasing factor (CRF) family and is a specific ligand for the CRF type 2 receptor. In the present study, we studied expression of Ucn3/SCP in the normal adrenal and adrenal tumors by radioimmunoassay and reverse transcriptase-polymerase chain reaction (RT-PCR). High concentrations of immunoreactive (IR)-Ucn3 were present in the normal portions of adrenal glands (4.2+/-0.51 pmol/g wet weight, mean+/-S.E.M., n = 14), and the levels were higher than those in the brain. IR-Ucn3 was also detected in the tumor tissues of aldosterone-secreting adenomas (6.2+/-0.6 pmol/g wet weight, n = 10), cortisol-secreting adenomas (5.0+/-1.2 pmol/g wet weight, n = 4), and pheochromocytomas (1.9+/-0.4 pmol/g wet weight, n = 7). Reverse phase high performance liquid chromatography showed that IR-Ucn3 in normal portions of adrenal glands and aldosterone-secreting adenomas was eluted mainly in the positions of Ucn3 and SCP with several minor peaks eluting earlier. The RT-PCR showed expression of Ucn3 mRNA in normal portions of adrenal gland (positive ratio; 4/4), aldosterone-secreting adenomas (3/4), cortisol-secreting adenomas (1/3) and pheochromocytomas (6/7). These findings indicate that Ucn3 is produced in normal adrenal and adrenal tumors (both adrenocortical tumors and pheochromocytomas), and suggest that Ucn3 acts as an autocrine or paracrine regulator in normal adrenal and adrenal tumors.

Adenoma↗
PubMed2005

Autocrine peptide mediators of cerebral endothelial cells and their role in the regulation of blood-brain barrier.

A unique feature of cerebral endothelial cells (CECs) is the formation of the blood-brain barrier (BBB), which contributes to the stability of the brain microenvironment. CECs are capable of producing several substances mediating endothelium-dependent vasorelaxation or vasoconstriction, regulating BBB permeability, and participating in the regulation of cell-cell interactions during inflammatory and immunological processes. The chemical nature of these mediators produced by CECs ranges from gaseous anorganic molecules (e.g. nitric oxide) through lipid mediators (e.g. prostaglandins) to peptides. Peptide mediators are a large and diverse family of bioactive molecules which can elicit multiple effects on cerebral endothelial functions. In this review, we summarize current knowledge of peptide mediators produced by CECs, such as adrenomedullin, angiotensin, endothelin and several others and their role in the regulation of BBB functions.

Animals↗
PubMed2004

Autocrine and paracrine actions of natriuretic peptides in the heart.

The natriuretic peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), are a family of polypeptide mediators exerting numerous actions in cardiovascular homeostasis. ANP and BNP are cardiac derived, being secreted and up-regulated in myocardium in response to many pathophysiological stimuli. CNP is an endothelium-derived mediator. The classical endocrine effects of ANP and BNP on fluid homeostasis and blood pressure, especially in conditions characterised by left ventricular dysfunction, are well recognised and extensively researched. However, there is accumulating evidence that, in addition to endocrine actions, ANP and BNP exhibit important autocrine and paracrine functions within the heart and coronary circulation. These include regulation of myocyte growth, inhibition of fibroblast proliferation and extracellular matrix deposition, a cytoprotective anti-ischaemic (preconditioning-like) function, and influences on coronary endothelium and vascular smooth muscle proliferation and contractility. Most if not all of these actions can be ascribed to particulate guanylyl cyclase activation because the ANP/BNP receptor, natriuretic peptide receptor (NPR)-A, has an intracellular guanylyl cyclase domain. Subsequent elevation of the intracellular second messenger cGMP may exert diverse physiological effects through activation of cGMP-dependent protein kinases (cGK), predominantly cGK-I. However, there appear to be other contributory mechanisms in several of these actions, including the augmentation of nitric oxide synthesis. These diverse actions may represent counterregulatory mechanisms in the pathophysiology of many cardiovascular diseases, not just those typified by left ventricular dysfunction. Ultimately, insights from the autocrine/paracrine actions of natriuretic peptides may provide routes to therapeutic application in cardiac diseases of natriuretic peptides and drugs that modify their availability.

Animals↗
PubMed2005

Production and autocrine/paracrine effects of endogenous insulin-like growth factor-1 in rat cardiac fibroblasts.

Insulin-like growth factor (IGF)-1 appears to play an important role in cardiac hypertrophy or remodeling. However, the role of endogenous IGF-1 in the growth of cardiac myocytes and fibroblasts remains unclear. This study investigated the major site of the production of cardiac IGF-1 and the local effects of endogenous IGF-1 secreted from cardiac cells. A significant expression of IGF-1 mRNA was found in cultured neonatal and adult rat cardiac fibroblasts, but not in myocytes. In addition, an in vivo examination by in situ hybridization histochemical analyses demonstrated the IGF-1 transcripts in the interstitial fibrotic tissue of the ventricle. Time-dependent secretion of IGF-1 protein was also observed in cultured cardiac fibroblasts. An antibody against IGF-1 decreased collagen synthesis in cardiac fibroblasts under basal conditions. Fibroblast-conditioned medium, as well as exogenous IGF-1, increased protein synthesis in cardiac myocytes, and this increase was inhibited by antibodies against IGF-1 and IGF-1 receptor, IGF binding protein-3, and IGF-1 receptor antagonist. These observations suggest that IGF-1 is produced and released mainly from cardiac fibroblasts and that endogenous IGF-1 promotes collagen synthesis by cardiac fibroblasts and hypertrophy of myocytes as an autocrine and a paracrine factor. Cardiac IGF-1 may function as an endogenous modulator of cardiac hypertrophy or remodeling.

Animals↗
PubMed2005

Functional expression of neuropeptide Y receptors in human neuroblastoma cells.

Expression of neuropeptide Y (NPY) receptors in human SK-N-MC neuroblastoma cells was investigated. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed that Y1, Y4, and Y5 receptors were expressed in these cells. Expression was confirmed by Western blot and immunocytochemistry demonstrated abundant presence of all three receptors on cell membranes. NPY peptide was also expressed in these cells, but other members of the larger peptide family (peptide YY and pancreatic polypeptide) were not expressed. Incubation with U0126, a specific mitogen-activated protein kinase (MAPK) inhibitor, decreased cell number in serum-free medium culture. Since NPY activates MAPK via different subtypes of NPY receptors, results suggest that endogenously expressed NPY may control proliferation of these cells through a paracrine/autocrine mechanism.

Autocrine Communication↗
PubMed2006

The role of vascular endothelial growth factor and its receptor Flk-1/KDR in promoting tumour angiogenesis in feline and canine mammary carcinomas: a preliminary study of autocrine and paracrine loops.

Vascular Endothelial Growth Factor (VEGF) and its receptor KDR are involved in the regulation of angiogenesis and are up-regulated in a number of tumours in humans and in particular, breast cancer. We therefore evaluated the prognostic potential of the angiogenetic process in feline and canine mammary carcinomas by the immunohistochemical assessment of VEGF expression and micro vessel density (MVD) quantification and examined the interplay between VEGF and KDR. These variables were related to some relevant clinicopathological parameters and to overall survival (OS). VEGF and KDR expression were evaluated in epithelial, stromal and endothelial compartments in order to identify autocrine and/or paracrine loops. In dogs an increased VEGF expression did not show any statistical correlation with the clinicopathological parameters examined and was not correlated to a poorer prognosis. MVD was found to be significantly correlated to the histologic type (P=0.04), tumour grading (P=0.02), and to the OS (P=0.01). In cats VEGF expression was significantly correlated to tumor grading (P=0.01) and OS (P=0.03), while no significant associations were found between MVD and the other parameters. VEGF and KDR were found to be detected on the epithelial, and/or endothelial and/or stromal cells of the carcinomas in both species, suggesting indications for some possible autocrine and paracrine loops. Our results encourage further studies on the possible prognostic role of VEGF and MVD in canine and feline mammary tumours and on the role of growth factors and their receptors in promoting tumour proliferation and an "angiogenetic shift". The VEGF/KDR system may play a role in malignant transformation and tumor progression.

Animals↗