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At least 631 records · Page 35Linked to original sources
PubMed2006

Trans-differentiation of alveolar epithelial type II cells to type I cells involves autocrine signaling by transforming growth factor beta 1 through the Smad pathway.

Type II alveolar epithelial cells (AEC II) proliferate and transdifferentiate into type I alveolar epithelial cells (AEC I) when the normal AEC I population is damaged in the lung alveoli. We hypothesized that signaling by transforming growth factor beta1 (TGF beta1), through its downstream Smad proteins, is involved in keeping AEC II quiescent in normal cells and its altered signaling may be involved in the trans-differentiation of AEC II to AEC I. In the normal lung, TGF beta1 and Smad4 were highly expressed in AEC II. Using an in vitro cell culture model, we demonstrated that the trans-differentiation of AEC II into AEC I-like cells began with a proliferative phase, followed by a differentiation phase. The expression of TGF beta1, Smad2, and Samd3 and their phosphorylated protein forms, and cell cycle inhibitors, p15(Ink4b) and p21(Cip1), was lower during the proliferative phase but higher during the differentiation phase. Furthermore, cyclin-dependent kinases 2, 4, and 6 showed an opposite trend of expression. TGF beta1 secretion into the media increased during the differentiation phase, indicating an autocrine regulation. The addition of TGF beta1 neutralizing antibody after the proliferative phase and silencing of Smad4 by RNA interference inhibited the trans-differentiation process. In summary, our results suggest that the trans-differentiation of AEC II to AEC I is modulated by signaling through the Smad-dependent TGF beta1 pathway by altering the expression of proteins that control the G1 to S phase entry in the cell cycle.

Animals↗
PubMed2000

Roles of insulin receptor substrate-1, phosphatidylinositol 3-kinase, and release of intracellular Ca2+ stores in insulin-stimulated insulin secretion in beta -cells.

The signaling pathway by which insulin stimulates insulin secretion and increases in intracellular free Ca(2+) concentration ([Ca(2+)](i)) in isolated mouse pancreatic beta-cells and clonal beta-cells was investigated. Application of insulin to single beta-cells resulted in increases in [Ca(2+)](i) that were of lower magnitude, slower onset, and longer lifetime than that observed with stimulation with tolbutamide. Furthermore, the increases in [Ca(2+)](i) originated from interior regions of the cell rather than from the plasma membrane as with depolarizing stimuli. The insulin-induced [Ca(2+)](i) changes and insulin secretion at single beta-cells were abolished by treatment with 100 nm wortmannin or 1 micrometer thapsigargin; however, they were unaffected by 10 micrometer U73122, 20 micrometer nifedipine, or removal of Ca(2+) from the medium. Insulin-stimulated insulin secretion was also abolished by treatment with 2 micrometer bisindolylmaleimide I, but [Ca(2+)](i) changes were unaffected. In an insulin receptor substrate-1 gene disrupted beta-cell tumor line, insulin did not evoke either [Ca(2+)](i) changes or insulin secretion. The data suggest that autocrine-activated increases in [Ca(2+)](i) are due to release of intracellular Ca(2+) stores, especially the endoplasmic reticulum, mediated by insulin receptor substrate-1 and phosphatidylinositol 3-kinase. Autocrine activation of insulin secretion is mediated by the increase in [Ca(2+)](i) and activation of protein kinase C.

Animals↗
PubMed2000

p38 MAPK and NF-kappa B collaborate to induce interleukin-6 gene expression and release. Evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system.

In cardiac myocytes, the stimulation of p38 MAPK by the MAPKK, MKK6, activates the transcription factor, NF-kappaB, and protects cells from apoptosis. In the present study in primary neonatal rat cardiac myocytes, constitutively active MKK6, MKK6(Glu), bound to IkappaB kinase (IKK)-beta and stimulated its abilities to phosphorylate IkappaB and to activate NF-kappaB. MKK6(Glu) induced NF-kappaB-dependent interleukin (IL)-6 transcription and IL-6 release in a p38-dependent manner. IL-6 protected myocardial cells against apoptosis. Like IL-6, TNF-alpha, which activates both NF-kappaB and p38, also induced p38-dependent IL-6 expression and release and protected myocytes from apoptotis. While TNF-alpha was relatively ineffective, IL-6 activated myocardial cell STAT3 by about 8-fold, indicating a probable role for this transcription factor in IL-6-mediated protection from apoptosis. TNF-alpha-mediated IL-6 induction was inhibited by a kinase-inactive form of the MAPKKK, TGF-beta activated protein kinase (Tak1), which is known to activate p38 and NF-kappaB in other cell types. Thus, by stimulating both p38 and NF-kappaB, Tak1-activating cytokines, like TNF-alpha, can induce IL-6 expression and release. Moreover, the myocyte-derived IL-6 may then function in an autocrine and/or paracrine fashion to augment myocardial cell survival during stresses that activate p38.

Animals↗
PubMed2001

Direct, autocrine and paracrine effects of cyclic stretch on growth of myocytes and fibroblasts isolated from neonatal rat ventricles.

Several studies have demonstrated that static stretch of cardiomyocytes induces cardiomyocyte hypertrophy. We investigated the effects of cyclic stretch, a more physiological stimulus, on protein synthesis and DNA synthesis of rat ventricular cardiomyocytes and cardiofibroblasts. Further-more, we investigated whether these effects are caused by autocrine mechanisms. In addition, we studied the paracrine influences of stretched cardiofibroblasts on cardiomyocyte growth. Short-term cyclic stretch (0-24 h) of cardiomyocytes induced a growth response indicative of cardiomyocyte hypertrophy, given the fact that increased rates of protein synthesis and DNA synthesis were accompanied by an elevated release of atrial natriuretic peptide into the culture medium. In cardiofibroblasts, short-term cyclic stretch also induced a growth response as indicated by an increased rate of protein synthesis and DNA synthesis. Furthermore, incubation of stationary cardiofibroblasts with conditioned medium derived from stretched cardiofibroblasts revealed an autocrine effect of stretch as illustrated by an increased rate of protein synthesis in stationary cardiofibroblasts. In analogy, there was an autocrine effect of stretch on stationary cardiomyocytes incubated with conditioned medium derived from stretched cardiomyocytes. Moreover, we observed a paracrine effect of the conditioned medium derived from stretched cardiofibroblasts on stationary cardiomyocytes. Thus, short-term cyclic stretch of cardiomyocytes and cardiofibroblasts induces growth responses that are the result of direct, autocrine, and paracrine effects. These autocrine/paracrine effects of stretch are most probably due to release of factors from stretched cells.

Animals↗
PubMed2000

PI 3-kinase signalling in platelets: the significance of synergistic, autocrine stimulation.

Phosphoinositide 3-kinases (PI 3Ks) play a key role in regulation of intracellular signalling and cellular function, including cell proliferation, apoptosis, chemotaxis, membrane trafficking and platelet activation. The PI 3Ks are grouped into three classes on the basis on their structure and in vitro substrate specificity. Class I are activated by a variety of agonists which mediate their effect through tyrosine kinase-linked or G-protein-linked receptors. In vivo class I PI 3Ks seem to preferentially phosphorylate the D3 hydroxyls of the inositol moiety of PtdIns(4,5)P2 to produce PtdIns(3,4,5)P3. However, class II PI 3Ks preferentially phosphorylate the D3 hydroxyl of PtdIns and PtdIns(4)P to produce PtdIns(3)P and PtdIns(3,4)P2, respectively. The late accumulation of PtdIns(3,4)P2 has been suggested to play an important role in irreversible platelet aggregation. In human platelets the class II PI 3K isoform HsC2-PI 3K is activated in an integrin alpha IIb beta 3 + fibrinogen-dependent manner. Class III PI 3Ks phosphorylate PtdIns to produce PtdIns(3)P, which play a crucial role in vesicular trafficking. Recent work has suggested that crosstalk between individual receptors and their downstream signal pathways play a central role in PI 3K signalling responses. In this review, we will concentrate on recent advances regarding the regulation of platelet PI 3Ks.

Autocrine Communication↗
PubMed2003

Concurrent responses elicited by isolated activation of platelet Gq-coupled receptors, in vitro: a novel approach for their separation and analysis.

This study tested the hypothesis that aggregation mediated by activation of a single G(q)-coupled receptor can be studied quantitatively if four concurrent but distinct components of the observed platelet response, autocrine stimulation, shape change (SC), aggregation and deaggregation, are separately measured. Responses mediated by two G(q)-coupled receptors, the TXA(2) and the P2Y(1), were assayed by a novel, kinetics-based turbidimetric approach. Blocking the autocrine stimulation with a cocktail of receptor antagonists revealed rapid and sustained SC that largely masked the aggregation. Mathematical removal of the SC contribution from the changes in optical density indicated that selective activation of either the TXA(2) or the P2Y(1) receptor was sufficient to induce a small aggregation (DeltaOD = 0.1-0.2) that was reversed rapidly by a concurrent deaggregation. Model-derived rate constants of SC, aggregation and deaggregation described the observed complex time course of their concurrency well. Laser light scattering aggregometry confirmed the rapid deaggregation of platelet aggregates following TXA(2) or P2Y(1) receptor-mediated formation. Saturable concentration response curves of net aggregation were elicited at EC(50) values 6-15 higher than those of SC. The utility of this approach was further demonstrated by the separation of the four components of the response mediated by concurrent 5-HT(2A) and alpha(2A)-adrenoceptor activation, as well as the P2Y(1) and alpha(2A)-adrenoceptor, and the autocrine stimulation and SC mediated by the 5-HT(2A) receptor. We propose that the novel approach described here is necessary to study the receptor pharmacology and the kinetics of concurrent platelet responses in vitro as demonstrated by platelet aggregation elicited by selective activation of the TXA(2) or the P2Y(1) receptors.

Autocrine Communication↗
PubMed2006

The tumor microenvironment: key to early detection.

The tumor microenvironment plays an important role equal to the tumor cell population in the progression of cancer. Consisting of stromal fibroblasts, inflammatory cells, components of the vasculature, normal epithelia, and extracellular matrix, the surrounding environment interacts or "cross-talks" with tumor cells through the release of growth factors, cytokines, proteases, and other bioactive molecules. Tumor growth, formation of new vascular networks, evasion of the host immune system, and invasion and metastasis are processes that co-evolve and become finely optimized and regulated within the tumor microenvironment. However, relatively recent reports on three areas of study have come together to add new levels of complexity to the tumor microenvironment. These include ectodomain shedding of proteins, shedding of membrane-derived vesicles, and novel roles for phospholipids. These dynamic changes that take place in the tumor microenvironment provide new avenues for study and for the early detection of cancer, whereas proteomic technologies provide the means to detect these unique proteins and lipids. Here we review the evolving concepts of the tumor microenvironment that, together with advances in proteomic technologies, hold the promise to facilitate the detection of early-stage cancer.

Allantois↗
PubMed2002

The role of interleukin 13 in classical Hodgkin lymphoma.

The Reed-Sternberg (RS) cells of classical Hodgkin lymphoma (cHL) produce several cytokines, which are thought to account for the unique clinical and pathologic features of this disease. We previously identified interleukin (IL)-13 expression as a common feature of cHL and have studied the potential role of this cytokine as an autocrine growth factor for RS cells. IL-13 and the IL-13-specific receptor chain (IL-13R alpha1) are frequently expressed in cHL-derived cell lines and in RS cells from biopsies of cHL tissues. In contrast, IL-13 expression in non-Hodgkin lymphoma (NHL) is uncommon. Neutralization of IL-13 in cultures of cHL-derived cell lines HDLM-2 and L-1236 leads to a dose-dependent inhibition of proliferation, and is associated with increased apoptosis in L-1236 cells. IL-13 neutralization also decreased activation of signal transducer and activator of transcription (STAT)6, an important mediator of IL-13 function. Moreover, STAT6 is often activated in RS cells from primary tumor samples, implying that IL-13 signaling is occurring in these cells in vivo. This review will describe the biologic activities of IL-13 in the immune system, and summarize the evidence implicating IL-13 as an autocrine growth factor for RS cells in cHL. Finally, we will discuss the potential influence of IL-13 on the reactive inflammatory infiltrate that is characteristic of cHL.

Animals↗
PubMed2003

Expression of chemokine receptor CXCR3 and its ligand, mig, in gastric and thyroid marginal zone lymphomas. Possible migration and autocrine mechanism.

Chemokine receptors mediate the migration of lymphocytes through the binding of ligands, and the expression is differentially regulated in lymphocyte subsets. CXCR3 is usually expressed in Th1 T cells, however, recently is reported to be expressed in B cell chronic lymphocytic leukemia, mucosa-associated lymphoid tissue type lymphoma (MALT) (extranodal marginal zone lymphoma), and other B cell non-Hodgkin lymphomas. Our study was designed to investigate the expression of CXCR3 and its ligand Mig, and their relationships in MALT using immunohistochemistry. In addition, CCR4, which is characteristic Th2 helper phenotype, and its ligand thymus and activation-regulated chemokine (TARC), were compared with CXCR3, as Th1 phenotype. We studied 14 cases of gastric B cell lymphoma [low-grade MALT, 5 cases; high-grade MALT, 5 cases; and diffuse large (DL), 4 cases] and 16 cases of thyroid B cell lymphoma [low-grade MALT, 4 cases; high-grade MALT, 5 cases; and DL, 7 cases]. CXCR3-expressing lymphoid cells were detected in all cases. In double immunostaining (CXCR3-CD20), gastric and thyroid low/high MALT showed CXCR3-positive neoplastic B cells, but DL, except two cases, did not. In DL, CXCR3-positive lymphoid cells were mainly reactive T-cells (CD3-positive cells). Mig was expressed mainly in stromal cells (histiocytes, macrophages, fibroblasts, and endothelial cells). In gastric lymphoma, low-grade MALT contained abundant Mig-strongly expressing cells, while staining in high-grade MALT and DL was mild. In thyroid lymphoma, staining was strong in low- and high-grade MALT, but moderate in DL. In double-staining, CXCR3-Mig-coexpressing lymphoma cells were abundant in high MALT of the stomach and thyroid, but rare in other subtypes. TARC-positive cells and CCR4-positive cells were rarely encountered in all cases. Our results indicate a tendency for low-grade MALT to contain CXCR3(+)Mig- lymphoma cells, high-grade to contain CXCR3(+)Mig+ and DL to contain CRCR3(-)Mig- lymphoma cells. We speculate that CXCR3 is associated with migration of lymphoma cells in low-grade MALT, and autocrine function in high-grade MALT, and not associated with any function in DL.

Aged↗
PubMed2004

Coexpression of CD40 and CD40L on B lymphoma and carcinoma cells: an autocrine anti-apoptotic role.

To evaluate a possible autocrine role of CD40L, the expression and functional activity of CD40L on NHL and breast carcinoma cell lines were investigated. Using flow cytometry, CD40 was consistently detectable at the surface of all 5 NHL cell lines tested. CD40L expression was detectable at the surface of DAUDI (54%, MFI 47) and BJAB (12%, MFI 32) cell lines, and marginally on the RAJI cell line (7%, MFI 30), while 4 of 5 NHL cell lines (DAUDI, RAJI, BJAB, BL70) had detectable CD40L mRNA. CD40 was expressed on T47D and BT20 breast carcinoma cell lines while CD40L was detectable on T47D (93%, MFI 137) only. Both BT20 and T47D had detectable CD40 mRNA, while CD40L mRNA was detectable only in the T47D cell line. CD40, but not CD40L, was detectable on 6 renal, 1 prostatic and 1 colon carcinoma cell lines. CD40L expressed on tumor cells was functional, as shown by its capacity to decrease drug-induced apoptosis on CD40 expressing NHL and breast carcinoma cell lines, while irradiated CD40L negative cell line (BT20) had no effect. Blocking CD40L antibody abrogated the protective effect of irradiated CD40L positive T47D cell line against drug-induced apoptosis on BL70 cell line, confirming that CD40L is functional in the DAUDI and T47D cell lines. Importantly, blocking CD40L antibody increased drug-induced apoptosis in CD40L positive cell lines but had no effect on the CD40L negative cell lines. CD40L is expressed on CD40 positive B NHL and breast carcinoma cell lines and induces an autocrine antiapoptotic signal when cells are exposed to cytotoxic agents.

Antibodies, Blocking↗
PubMed2004

Inhibition of both the autocrine and the paracrine growth of human leukemia with a fully human antibody directed against vascular endothelial growth factor receptor 2.

Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) have been implicated in promoting solid tumor growth and metastasis via stimulating tumor-associated angiogenesis. Here we show that certain "liquid" tumors such as acute myeloid leukemia not only produce VEGF but also express functional VEGFR, resulting in an autocrine loop for tumor growth and propagation. In addition, the leukemia-derived VEGF can also stimulate the production of growth factors, including interleukin 6 (IL6) and granulocyte-macrophage colony stimulating factor (GM-CSF), by human endothelial cells, which in turn further promotes the growth of leukemia cells (the paracrine loop). A fully human anti-VEGFR2 (or kinase insert domain-containing receptor, KDR) antibody, IMC-2C6, strongly blocks KDR/VEGF interaction and neutralizes VEGF-stimulated activation of KDR in endothelial cells. In a system where leukemia cells are co-cultured with endothelial cells, IMC-2C6 inhibits both the production of IL6 and GM-CSF by endothelial cells and the growth of leukemia cells. Finally, IMC-2C6 effectively blocks VEGF-induced migration of KDR+ human leukemia cells, and when administered in vivo, significantly prolonged survival of mice inoculated with KDR+ human leukemia cells. Taken together, our data suggest that anti-KDR antibodies may have broad applications in the treatment of both solid tumors and certain types of leukemia.

Animals↗
PubMed2006

Disease-specific expression of VEGF and its receptors in AML cells: possible autocrine pathway of VEGF/type1 receptor of VEGF in t(15;17) AML and VEGF/type2 receptor of VEGF in t(8;21) AML.

Various angiogenic factors, such as vascular endothelial growth factor (VEGF) and an associated molecule, placenta growth factor (PlGF), are thought to be important for normal and malignant hematopoiesis. This study examined mRNA expression of VEGF, PlGF and receptors for these molecules in AML cells and identified the disease-specific patterns of expression. AML M3 having t(15;17) abnormality showed highest expression of VEGF and VEGF receptor type 1 (VEGFR1), suggesting the autocrine pathway of VEGF-VEGFR1. Then, t(8;21) AML demonstrated augmented expression of VEGF and VEGF receptor type 2 (VEGFR2), suggesting VEGF-VEGFR2 autocrine pathway. Then, addition of VEGFR2 kinase inhibitor in Kasumi-1, a t(8;21) AML cell line, resulted in marked inhibition of cell growth, although growth inhibitory effect of R2 kinase inhibitor to HL-60 was marginal. In addition, cell cycle analysis study showed S-phase cell population reduction by R2 kinase inhibitor in Kasumi-1, but not in HL-60. This observation is thought to be the rationale for novel molecular target therapy directed to angiogenic molecules.

Adult↗
PubMed2006

Autocrine effects of endothelin on in vitro proliferation of vascular smooth muscle cells from spontaneously hypertensive and normotensive rats.

According to previous studies, endothelin-1 (ET-1) is the most potent growth factor in the regulation of vascular smooth muscle cell (VSMC) proliferation in spontaneously hypertensive rats (SHR). To evaluate if the dominant effect of ET-1-induced VSMC proliferation is achieved by autocrine regulation, aortic smooth muscle cells from four-week-old SHR and WKY (Wistar-Kyoto) rats were cultured in 24-well dishes, and the effects of ET-1 on VSMC proliferation were determined by (a) 3H-thymidine incorporation assays with different ET-1 blocking treatments, including a specific anti-ET-1 antibody; BQ-123, an ETA receptor blocker; and BQ-788, an ETB receptor blocker; and (b) examining the ET-1 blockade on the effects of treatment with other growth factors, including thrombin and angiotension II (AT-II). These results demonstrated that the anti-ET-1 antibody, BQ-123, BQ-788, and BQ-123 plus BQ-788 all caused dose-dependent inhibition of proliferation. A 90% inhibitory effect was observed at the maximum doses used except for BQ-123. The ET-1 receptor blockers inhibited thrombin-induced VSMC growth; however, they did not efficiently inhibit AT-II-induced VSMC growth. These results indicate that the autocrine effects of ET-1 play a predominant role in the proliferation of VSMCs from SHR and WKY rats. They also suggest that thrombin-induced VSMC growth is mediated by the autocrine effects of ET-1, and angiotensin II-induced VSMC growth is mediated by other signal pathways.

Angiotensin II↗
PubMed2005

Eosinophils from asthmatics release IL-5 in an autocrine fashion to prevent apoptosis through upregulation of Bcl-2 expression.

Interleukin (IL)-5 plays an important role in maintaining the survival of eosinophils via the specific alpha-subunit of its receptor. Apoptosis, a form of programmed cell death, is thought to represent a mechanism that promotes the resolution of eosinophilic inflammation in asthma. The aim of our present study is to investigate whether IL-5 acts in an autocrine fashion on eosinophil apoptosis in asthmatics. Immunoreactivities of intracellular IL-5 and IL-5 receptor alpha-subunit (Ralpha) were detected uniquely on the eosinophils. The magnitude of IL-5 and IL-5 Ralpha expression on eosinophils was significantly higher in asthmatics than that of normal subjects (p<0.05) determined by flow cytometry. Apoptosis of eosinophils was measured by the propidium iodide staining method and DNA ladder. The percent of apoptotic eosinophils from asthmatics was significantly increased by coincubation with anti-hIL-5 Ralpha Ab (0.1, 0.5, and 2.5 microg/mL) for 1, 2, or 16 hours than was those of corresponding controls (p<0.05, n=8). However, there was no significant effect of anti-hIL-5 Ralpha Ab on eosinophil apoptosis in normal subjects. Furthermore, the expression of B-cell lymphoma-2 (Bcl-2) proteins was significantly inhibited by the anti-hIL-5 Ralpha Ab or antisense IL-5 oligonucleotides in asthmatics (p<0.05, n=8), but there was no significant change in eosinophils from normal subjects. This study demonstrates that eosinophils from asthmatics release IL-5 in an autocrine fashion to act on their own IL-5 receptors in prevention of apoptosis through the upregulation of Bcl-2 expression.

Adult↗
PubMed1998

Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis.

FGF-2 and VEGF are potent angiogenesis inducers in vivo and in vitro. Here we show that FGF-2 induces VEGF expression in vascular endothelial cells through autocrine and paracrine mechanisms. Addition of recombinant FGF-2 to cultured endothelial cells or upregulation of endogenous FGF-2 results in increased VEGF expression. Neutralizing monoclonal antibody to VEGF inhibits FGF-2-induced endothelial cell proliferation. Endogenous 18-kD FGF-2 production upregulates VEGF expression through extracellular interaction with cell membrane receptors; high-Mr FGF-2 (22-24-kD) acts via intracellular mechanism(s). During angiogenesis induced by FGF-2 in the mouse cornea, the endothelial cells of forming capillaries express VEGF mRNA and protein. Systemic administration of neutralizing VEGF antibody dramatically reduces FGF-2-induced angiogenesis. Because occasional fibroblasts or other cell types present in the corneal stroma show no significant expression of VEGF mRNA, these findings demonstrate that endothelial cell-derived VEGF is an important autocrine mediator of FGF-2-induced angiogenesis. Thus, angiogenesis in vivo can be modulated by a novel mechanism that involves the autocrine action of vascular endothelial cell-derived FGF-2 and VEGF.

3T3 Cells↗
PubMed2001

Autocrine stimulation of human pancreatic duct-like development by soluble isoforms of epimorphin in vitro.

Epimorphin was recently described as a mesenchymal factor modulating morphogenesis of murine mammary ducts, skin, liver, and lung in vitro. In this study epimorphin was analyzed in a human, pancreatic adenocarcinoma cell line (A818-6) which develops single layer epithelial hollow spheres resembling normal pancreatic ductal structures in vitro. Soluble 34- and 31-kD isoforms of epimorphin were found in the culture supernatant of A818-6 cells. In lysates of A818-6 cells we detected the 34-and 31-kD isoforms and the dimers, and in lysates of fibroblasts the 150-kD tetramers of epimorphin additionally. A neutralizing monoclonal antibody against epimorphin (MC-1) efficiently blocked the development of hollow sphere structures from A818-6 cells. Coculture of A818-6 cells with fibroblasts stimulated the development of hollow sphere structures in general and increased differentiation in 5-6-d-old hollow spheres. A818-6 hollow sphere development in the presence of fibroblasts was also blocked by MC-1. In this novel system for human duct-like differentiation of pancreatic epithelial cells, we provide evidence for an autocrine and paracrine function of epimorphin as a major mediator for morphogenesis.

Adenocarcinoma↗
PubMed2001

Oncogenic Ras-induced proliferation requires autocrine fibroblast growth factor 2 signaling in skeletal muscle cells.

Constitutively activated Ras proteins are associated with a large number of human cancers, including those originating from skeletal muscle tissue. In this study, we show that ectopic expression of oncogenic Ras stimulates proliferation of the MM14 skeletal muscle satellite cell line in the absence of exogenously added fibroblast growth factors (FGFs). MM14 cells express FGF-1, -2, -6, and -7 and produce FGF protein, yet they are dependent on exogenously supplied FGFs to both maintain proliferation and repress terminal differentiation. Thus, the FGFs produced by these cells are either inaccessible or inactive, since the endogenous FGFs elicit no detectable biological response. Oncogenic Ras-induced proliferation is abolished by addition of an anti-FGF-2 blocking antibody, suramin, or treatment with either sodium chlorate or heparitinase, demonstrating an autocrine requirement for FGF-2. Oncogenic Ras does not appear to alter cellular export rates of FGF-2, which does not possess an NH(2)-terminal or internal signal peptide. However, oncogenic Ras does appear to be involved in releasing or activating inactive, extracellularly sequestered FGF-2. Surprisingly, inhibiting the autocrine FGF-2 required for proliferation has no effect on oncogenic Ras-mediated repression of muscle-specific gene expression. We conclude that oncogenic Ras-induced proliferation of skeletal muscle cells is mediated via a unique and novel mechanism that is distinct from Ras-induced repression of terminal differentiation and involves activation of extracellularly localized, inactive FGF-2.

Animals↗