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At least 703 records · Page 39Linked to original sources
PubMed1997

Immunoreactive alpha-melanotropin as an autocrine effector in human melanoma cells.

Melanotropin is a peptide having several functions, including the stimulation of melanogenesis and the modulation of proliferation of melanocytes and melanoma cells. It acts through binding to high-affinity receptors of the melanocortin-1 subtype, exclusively expressed in cells of the melanocytic lineage. Elevated levels of immunoreactive alpha-melanotropin were previously reported in melanoma cell lines, tumours and plasma from patients with melanoma. Here, we show that this high ectopic production of melanotropin is restricted to melanoma and non-pituitary tumours with the same neuroectodermic origin. The occurrence of a melanotropin-specific autocrine loop was further investigated in human melanoma cells. Immunoreactive alpha-melanotropin was spontaneously released from a melanoma cell line (HBL) expressing melanotropin receptors on the cell surface. This release was significantly increased in the presence of melanotropin-related peptides such as corticotropin-(4-10)-peptide and beta-melanotropin, competing for binding to the melanotropin receptor and was directly correlated to the displacement potential of these peptides. Both spontaneous and induced releases of immunoreactive alpha-melanotropin could be blocked at low temperatures, suggesting the involvement of intracellular protein movement in the release mechanism. The release of immunoreactive alpha-melanotropin was not significant in melanoma cells expressing very low levels of melanotropin receptors (IGR3) or in non-melanoma cells (SCC1). However, upon expression of the melanocortin-1 receptor cDNA into IGR3 cells, spontaneous and competition-induced releases of immunoreactive alpha-melanotropin were both increased and also blocked at low temperatures. This observation further underlines a role for the melanotropin receptor in the release of immunoreactive alpha-melanotropin. These experiments indicate that an autocrine loop between the melanocortin-1 receptor and immunoreactive alpha-melanotropin may be functional in human melanoma cells.

Adult↗
PubMed1996

Autocrine role of insulin-like growth factor II secretion by the rat choroid plexus.

Insulin-like growth factor II (IGF-II) is expressed and secreted by the choroid plexus and has been suggested to act as a trophic factor in the adult mammalian central nervous system. The aim of the present study was to investigate whether IGF-II has an autocrine role in the choroid plexus. Using in situ hybridization we demonstrate that IGF-II is primarily expressed in the epithelium of adult rat choroid plexus. Conditioned medium from primary cultures of purified rat choroid plexus epithelial cells, intact choroid plexus tissue, as well as rat CSF, displaced IGF-II binding to a 23 HMM melanoma cell line in an IGF-II radioreceptor assay. The presence of IGF-II and IGF binding protein-2 in conditioned medium was shown by Western immunoblot. The mitotic activity in choroid plexus epithelial cell cultures was quantified by immunohistochemical staining of bromodeoxyuridine incorporated into cell nuclei. A monoclonal antibody towards IGF-II inhibited cell division by 35%, while IGF-I increased the number of stained nuclei by 75%. Basic fibroblast growth factor stimulated cell division at low concentrations, but had no effect at high concentrations. Growth hormone had no effect. We conclude that IGF-II in the choroid plexus could have an autocrine role in the regulation of choroid plexus epithelial cell growth.

Animals↗
PubMed1994

Autocrine enhancement of leukotriene synthesis by endogenous leukotriene B4 and platelet-activating factor in human neutrophils.

1. Platelet-activating factor (PAF) and leukotriene B4 (LTB4), two potent lipid mediators synthesized by activated neutrophils, are known to stimulate several neutrophil functional responses. In this study, we have determined that endogenous LTB4 and PAF exert autocrine effects on LT synthesis, as well as the underlying mechanism involved. 2. Pretreatment of neutrophils with either pertussis toxin (PT), or with receptor antagonists for LTB4 and PAF, resulted in an inhibition of LT synthesis induced by calcium ionophore, A23187. This inhibition was most marked at submaximal (100-300 nM) A23187 concentrations, whilst it was least at ionophore concentrations which induce maximal LT synthesis (1-3 microM). Thus newly-synthesized PAF and LTB4 can enhance LT synthesis induced by A23187 under conditions where the LT-generating system is not fully activated. 3. In recombinant human (rh) granulocyte-macrophage colony-stimulating factor (GM-CSF)-primed neutrophils, LT synthesis in response to chemoattractants (fMet-Leu-Phe or rhC5a) was also significantly inhibited by the LTB4 receptor antagonist, and to a lesser extent by PAF receptor antagonists. 4. Further investigation revealed that LTB4 and/or PAF exert their effects on LT synthesis via an effect on arachidonic acid (AA) availability, as opposed to 5-lipoxygenase (5-LO) activation. Indeed, the receptor antagonists, as well as PT, inhibited LT synthesis and AA release to a similar extent, whereas 5-LO activation (assessed with an exogenous 5-LO substrate) was virtually unaffected under the same conditions. Accordingly, we showed that addition of exogenous LTB4 could enhance AA availability in response to chemoattractant challenge in rhGM-CSF-primed cells, without significantly affecting the 5-LO activation status. Our data show that newly-generated PAF and LTB4 have the ability to positively feedback on LT synthesis by acting at the level of the phospholipase A2/re-esterification component of the LT biosynthetic pathway in neutrophils. Such autocrine affects are likely to represent an important amplification step of LT synthesis, and may as such contribute to the rapid onset, as well as to the evolution, of inflammatory responses.

Amino Acid Sequence↗
PubMed2005

Autocrine and paracrine functions of vascular endothelial growth factor (VEGF) in renal tubular epithelial cells.

BACKGROUND: VEGF secreted by organ parenchymal cells controls vascularization by recruiting endothelial cells and supporting their proliferation. In the developing kidney VEGF-expressing epithelial cells also express VEGF receptors. We showed that VEGF stimulates tubulogenesis in addition to promoting vascularization in metanephric explants. Since explants are grown in serum-free media and are not perfused, we hypothesized that VEGF secreted by renal epithelia may induce their proliferation in an autocrine manner and chemoattract endothelial cells. METHODS: To test these hypotheses, we analyzed VEGF-mediated responses in vitro using several renal epithelial cell lines [immortalized rat proximal tubular cells (IRPT), transformed mouse proximal tubular cells (tsMPT), and normal rat kidney cells (NRK-52E)] expressing VEGF receptors (VEGFR). RESULTS: We demonstrated that VEGFR-2 phosphorylates upon human recombinant VEGF (rhVEGF) exposure, indicating that VEGFR-2 is the signaling receptor. All three cell lines secreted VEGF into the media as indicated by enzyme-linked immunosorbent assay (ELISA) and Western blotting. We showed that these tubular epithelial cells chemoattract endothelial cells when cocultured in vitro and that the chemoattraction is abolished by anti-VEGF neutralizing antibody. rhVEGF (10 ng/mL) induced a mitogenic effect similar to 10% fetal bovine serum (FBS) as assessed by H(3)-thymidine incorporation and elicited 30% decrease in apoptosis as determined by annexin V-fluorescein isothiocyanate (FITC) staining. CONCLUSION: These in vitro studies indicate that (1) tubular epithelial cells chemoattract endothelial cells in a paracrine fashion by secreting VEGF, and (2) VEGF stimulates proliferation and promotes survival of renal epithelial cells in an autocrine manner via VEGFR-2. Taken together, our results suggest that VEGF supports the growth of renal epithelia in addition to mediating kidney vascularization.

Animals↗
PubMed1992

Epstein-Barr virus-transformed B lymphocytes produce low molecular mass molecules with autocrine growth factor and competence factor activity.

A human Epstein-Barr virus (EBV)-positive lymphoblastoid B cell line, named BA-D10-4, produces a factor of a molecular mass less than 10 kDa that promotes cell proliferation of both BA-D10-4 cells and other human T or B lymphoid cell lines, either EBV-positive or -negative. The factor synergizes with higher molecular mass autocrine growth factors and makes both BA-D10-4 cells and B cell lines from Burkitt's lymphoma, but not cells from T cell leukemia, more responsive to interleukin-1 and interleukin-6. Therefore, this low molecular mass factor seems to be an autocrine growth factor per se and to have the characteristics of a competence factor.

B-Lymphocytes↗
PubMed2004

Autocrine and paracrine regulation of melanocytes in human skin and in pigmentary disorders.

Recently melanogenic paracrine or autocrine cytokine networks have been discovered in vitro between melanocytes and other types of skin cells. These include endothelin (ET)-1, granulocyte macrophage colony stimulating factor, membrane-type stem cell factor (SCF) and growth-related oncogene-alpha for interactions between keratinocytes and melanocytes, and hepatocyte growth factor and soluble type SCF for interactions between fibroblasts and melanocytes. These networks are also associated with corresponding receptors expressed on melanocytes, including ET B receptor and the SCF receptor, c-KIT. Consistent with in vitro findings on the melanogenic paracrine or autocrine cytokine networks, we have found that the up- or down-regulation of such networks is intrinsically involved in vivo in the stimulation of melanocyte functions in several epidermal hyper- or hypo-pigmentary disorders. These are ET-1/ET B receptor as well as membrane type SCF/c-KIT for ultraviolet B-melanosis, granulocyte macrophage colony stimulating factor for ultraviolet A-melanosis, ET-1/ET B receptor as well as membrane type SCF for lentigo senilis, growth related oncogene-alpha for Riehl's melanosis, sphingosylphosphorylcholine for hyperpigmentation in atopic dermatitis, ET-1 for seborrhoeic keratosis, soluble type SCF as well as hepatocyte growth factor for dermatofibroma and café-au-lait macules, and c-KIT for vitiligo vulgaris. These unveiled regulatory mechanisms involved in the abnormal up- or down-regulated levels of lesional melanocyte function provide new insights into therapeutic tools utilizing blockage of responsible cytokine networks.

Down-Regulation↗
PubMed1998

Evidence for PACAP to be an autocrine factor on gonadotrope cells.

In summary, PACAP actions on gonadotrope cells are schematically outlined in FIGURE 5. PACAP is produced by and secreted from gonadotropes. The peptide increases LH release in an autocrine manner by a direct stimulatory action via the PACAP receptor and, as suggested by Culler and Paschall, by amplification of the LHRH stimulus. Hence, our data support the hypothesis that PACAP acts as an autocrine regulator on gonadotrope cell function.

Animals↗
PubMed2005

Autocrine activation of nicotinic acetylcholine receptors contributes to Ca2+ spikes in mouse myotubes during myogenesis.

It is widely accepted that nicotinic acetylcholine receptor (nAChR) channel activity controls myoblast fusion into myotubes during myogenesis. In this study we explored the possible role of nAChR channels after cell fusion in a murine cell model. Using videoimaging techniques we showed that embryonic muscle nAChR channel openings contribute to the spontaneous transients of intracellular concentration of Ca2+ ([Ca2+]i) and to twitches characteristic of developing myotubes before innervation. Moreover, we observed a choline acetyltransferase immunoreactivity in the myotubes and we detected an acetylcholine-like compound in the extracellular solution. Therefore, we suggest that the autocrine activation of nAChR channels gives rise to [Ca2+]i spikes and contractions. Spontaneous openings of the nAChR channels may be an alternative, although less efficient, mechanism. We report also that blocking the nAChRs causes a significant reduction in cell survival, detectable as a decreased number of myotubes in culture. This led us to hypothesize a possible functional role for the autocrine activation of the nAChRs. By triggering mechanical activity, such activation could represent a strategy to ensure the trophism of myotubes in the absence of nerves.

Acetylcholine↗
PubMed2004

Src family kinase inhibitors block amphiregulin-mediated autocrine ErbB signaling in normal human keratinocytes.

c-Src potentiates proliferation, survival, and invasiveness in response to epidermal growth factor (EGF) in human mammary carcinoma cells. Tyrosine (Tyr) 845 of ErbB1 is phosphorylated by Src and has been implicated in control of malignant behavior. Although several lines of evidence also suggest important interactions of ErbB and Src family kinase signaling in normal epithelial cells, little is known about the mechanism of this interaction. Studying normal human keratinocytes (NHKs), here we demonstrate strong expression of the Src family kinases Src, Yes, and Fyn; Src family kinase-dependent stimulation of Tyr 845 by EGF; and potent inhibition of NHK proliferation and migration by two Src family kinase inhibitors PP1 and PD173952. EGF-stimulated extracellular signal-regulated kinase (ERK) phosphorylation occurred at much lower concentrations of EGF than required to phosphorylate Tyr 845. Moreover, the effect of Src family kinase inhibitors on EGF-stimulated ERK phosphorylation was transient, prompting a search for other targets of Src family kinase action. By enzyme-linked immunosorbent assay analysis, we found that three different Src family kinase inhibitors [6-(2,6-dichlorophenyl)-8-methyl-2-(4-morpholin-4-ylphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (PD173952), 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1), and 2-oxo-3-(4,5,6,7-tetrahydro-1H-indol-2-ylmethylene)-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (SU6656)] markedly inhibited elaboration of soluble amphiregulin by NHKs. The ErbB inhibitor PD158780 and the mitogen-activated protein kinase kinase inhibitor U0126 also markedly inhibited NHK proliferation, migration, and amphiregulin production. Together, these observations demonstrate that one or more Src family kinases act upstream as well as downstream of ErbB1 to promote amphiregulin-dependent autocrine stimulation of NHKs and suggest that autocrine NHK proliferation is more dependent upon ERK activation than upon Tyr 845 phosphorylation.

Amphiregulin↗
PubMed1989

Autocrine induction of collagenase by serum amyloid A-like and beta 2-microglobulin-like proteins.

Two autocrine proteins of 14 and 12 kilodaltons that induce the synthesis of rabbit fibroblast collagenase were identified. The proteins were purified from serum-free culture medium taken from rabbit synovial fibroblasts stimulated with phorbol myristate acetate. The amino-terminal sequences of the 14- and 12-kilodalton species were approximately 60 to 80 percent homologous with serum amyloid A and beta 2 microglobulin, respectively. The polyacrylamide gel-eluted proteins retained the ability to induce collagenase synthesis in rabbit and human fibroblasts. These autocrine proteins may provide a means to modulate collagenase synthesis in normal remodeling as well as in inflammation and disease states.

Amino Acid Sequence↗
PubMed1996

Interleukin-1 alpha production during Rickettsia rickettsii infection of cultured endothelial cells: potential role in autocrine cell stimulation.

Rickettsia rickettsii infection results in numerous responses by cultured endothelial cells, among them a rapid, transient increase in steady-state levels of tissue factor mRNA (L.A. Sporn, P.J. Haidaris, R.-J. Shi, Y. Nemerson, D.J. Silverman, and V.J. Marder, Blood 83:1527-1534, 1994). In this study, production of interleukin-1 (IL-1) was measured during infection and its potential role in autocrine cell stimulation was investigated. A fivefold increase in levels of IL-1 alpha antigen was measured in cell lysate samples by enzyme-linked immunosorbent assay at 18 h of infection. The majority of IL-1 alpha remained cell associated, as no significant increase was detected in culture medium. No IL-1 beta antigen was detected in cell lysates or culture medium from either control or infected cultures. A dramatic increase in the levels of IL-1 alpha mRNA occurred following infection, as measured by reverse transcriptase PCR, which revealed the appearance of the expected 421-kb product with RNA extracted from cells infected for 4 h and no detectable product from control cell samples. The presence of functional, cell-associated IL-1 alpha activity in infected cells was confirmed, following disruption, by the ability of the infected cells to induce tissue factor expression in target endothelial cells. Such induction was eliminated by pretreatment of the disrupted cell samples with neutralizing antibodies against IL-1 alpha but not against IL-1 beta. To investigate whether endogenously produced IL-1 participates in the stimulation of tissue factor expression, neutralizing antibodies against IL-1 or the IL-1 receptor antagonist were added to culture medium during infection. Both anti-IL-1 alpha and the IL-1 receptor antagonist resulted in approximately 40% inhibition of tissue factor expression, thus implicating IL-1 alpha in autocrine cell stimulation.

Antibodies, Blocking↗
PubMed2002

Autocrine and exocrine regulation of interleukin-10 production in THP-1 cells stimulated with Borrelia burgdorferi lipoproteins.

We have recently demonstrated that interleukin-10 (IL-10), produced by THP-1 monocytes in response to Borrelia burgdorferi lipoproteins, dampens the production of concomitantly elicited inflammatory cytokines. Thus, IL-10 could potentially down-regulate inflammatory and microbicidal effector mechanisms of the innate immune response to a B. burgdorferi infection, facilitating the establishment of the spirochete. To understand the mechanism(s) implicated in the regulation of the synthesis and release of IL-10 during early infection, we investigated the autocrine effects of IL-6, IL-12, tumor necrosis factor alpha (TNF-alpha), and IL-10 itself, as well as the exocrine effect of IFN-gamma on the production of macrophage-derived IL-10 with lipoprotein as a stimulant. In addition, in view of the differences in the receptor and signal transduction pathways of lipopolysaccharide (LPS) and bacterial lipoproteins, we also investigated the effects described above with LPS as a stimulant. The THP-1 human monocytic cell line and purified recombinant lipidated OspA (L-OspA) were used as the model target cell and stimulant, respectively. TNF-alpha increased the production of IL-10, as elicited by lipoproteins. The production of IL-10 by THP-1 cells stimulated with L-OspA was autoregulated by a negative feedback mechanism involving the IL-10 receptor (IL-10R). Exogenous IFN-gamma significantly inhibited the production of IL-10. Both autocrine (IL-10) and exocrine (IFN-gamma) inhibition of IL-10 production resulted in an increase in the production of the proinflammatory cytokines IL-6 and IL-12. The same results were obtained when the stimulant was LPS. The results further illustrate that IL-10 may play a pivotal role in Lyme disease pathogenesis. Moreover, the regulation of its production with lipoprotein as a stimulant is indistinguishable from that observed when LPS acts as a stimulant.

Antigens, Surface↗
PubMed1994

Replacement of interleukin-2 (IL-2)-generated mitogenic signals by a mink cell focus-forming (MCF) or xenotropic virus-induced IL-9-dependent autocrine loop: implications for MCF virus-induced leukemogenesis.

In earlier studies, we have shown that superinfection of an interleukin-2 (IL-2)-dependent, Moloney murine leukemia virus (MoMuLV)-induced rat T-cell lymphoma line (4437A) with mink cell focus-forming (also called polytropic) murine retroviruses induces rapid progression to IL-2-independent growth. In this report, we present evidence that the vast majority (> 90%) of the IL-2-independent lines established from polytropic or xenotropic virus-infected 4437A cells carry provirus insertions in the 3' untranslated region of the IL-9 receptor gene (Gfi-2 [for growth factor independence-2]/IL-9R). Prior to superinfection, the cells express neither IL-9 nor IL-9R. Following superinfection and provirus insertion in the Gfi-2/IL-9R locus, the cells express high levels of mRNA transcripts with a truncated 3' untranslated region which are predicted to encode the normal IL-9R protein product. The same IL-2-independent cells also express IL-9 which is induced by an insertional mutagenesis-independent mechanism. The establishment of an IL-9-dependent autocrine loop was sufficient to render the cells IL-2 independent, as suggested by the finding that 4437A cells, expressing a stably transfected Gfi-2/IL-9R construct, do not require IL-2 when maintained in IL-9-containing media. Additional experiments designed on the basis of these results showed that IL-9 gene expression is induced rapidly following the infection of 4437A cells by polytropic or xenotropic viruses and occurs in the absence of selection for IL-2-independent growth. Taken together, these data suggest that infection of 4437A cells by mink cell focus-forming or xenotropic viruses induces the expression of IL-9, which in turn rapidly selects the cells expressing the IL-9 receptor through an insertional mutagenesis-dependent mechanism. Given that both the polytropic and xenotropic viruses can induce the IL-9-dependent autocrine loop, the reduced ability of the xenotropic viruses to rapidly induce IL-2 independence in culture and tumors in animals is likely to be the result of their lower growth rates.

Amino Acid Sequence↗
PubMed2001

Human herpesvirus 8 (HHV-8)-encoded cytokines induce expression of and autocrine signaling by vascular endothelial growth factor (VEGF) in HHV-8-infected primary-effusion lymphoma cell lines and mediate VEGF-independent antiapoptotic effects.

The potential roles of human herpesvirus 8 (HHV-8) cytokines in HHV-8 pathogenesis were investigated by determining the expression of the HHV-8 chemokines viral macrophage inflammatory protein 1A (vMIP-1A) and vMIP-1B in primary effusion lymphoma (PEL)-derived cell lines and examining the signaling activities of these chemokines and HHV-8-encoded vIL-6 in these cells. Secreted vMIP-1A and vMIP-1B were detected in biologically significant concentrations following tetradecanoyl phorbol acetate treatment, which induces productive replication. vIL-6 and vMIP-1A, added exogenously to cultures of four different PEL cell lines, induced the expression of vascular endothelial growth factor type B (VEGF-B) and VEGF-A, respectively. These cells were found to express VEGF receptor 1 (Flt-1) protein, and signaling by recombinant VEGF-A(165) was demonstrated for two of the PEL cell lines, indicating the potential for autocrine, as well as paracrine, effects of viral cytokine-induced VEGF. In addition, vMIP-1A and vMIP-1B, but not VEGF-A(165), were found to inhibit chemically induced apoptosis in PEL cells. Our data suggest that vIL-6 and vMIP-1A may influence PEL through VEGF autocrine and paracrine signaling that promotes PEL cell growth and extravascular effusion and that vMIP-1A and vMIP-1B can act independently of VEGF as antiapoptotic factors.

Animals↗
PubMed2005

Aberrant activation of the interleukin-2 autocrine loop through the nuclear factor of activated T cells by nonleukemogenic human T-cell leukemia virus type 2 but not by leukemogenic type 1 virus.

Human T-cell leukemia virus type 1 (HTLV-1) but not HTLV-2 is associated with adult T-cell leukemia. We found that HTLV-2 Tax2 protein stimulated reporter gene expression regulated by the interleukin (IL)-2 promoter through the nuclear factor of activated T cells (NFAT) in a human T-cell line (Jurkat). However, the activity of HTLV-1 Tax1 was minimal in this system. T-cell lines immortalized by HTLV-2 but not HTLV-1 constitutively exhibited activated NFAT in the nucleus and constitutively expressed IL-2 mRNA. Cyclosporine A, an inhibitor of NFAT activation, abrogated the induction of IL-2 mRNA in HTLV-2-immortalized T-cell lines and concomitantly inhibited cell growth. This growth inhibition was rescued by the addition of IL-2 to the culture. Furthermore, anti-IL-2 receptor antibodies significantly reduced the proliferation of HTLV-2-infected T-cell lines but not that of HTLV-1-infected cells. Our results suggest that Tax2 activates an IL-2 autocrine loop mediated through NFAT that supports the growth of HTLV-2-infected cells under low-IL-2 conditions. This mechanism would be especially important in vivo, where this autocrine mechanism establishes a nonleukemogenic life-long HTLV-2 infection. The results also suggest that differences in long-term cytokine production between HTLV-1 and HTLV-2 infection are another factor for the differences in pathogenesis.

Base Sequence↗
PubMed2006

Constitutive ALK5-independent c-Jun N-terminal kinase activation contributes to endothelin-1 overexpression in pulmonary fibrosis: evidence of an autocrine endothelin loop operating through the endothelin A and B receptors.

The signal transduction mechanisms generating pathological fibrosis are almost wholly unknown. Endothelin-1 (ET-1), which is up-regulated during tissue repair and fibrosis, induces lung fibroblasts to produce and contract extracellular matrix. Lung fibroblasts isolated from scleroderma patients with chronic pulmonary fibrosis produce elevated levels of ET-1, which contribute to the persistent fibrotic phenotype of these cells. Transforming growth factor beta (TGF-beta) induces fibroblasts to produce and contract matrix. In this report, we show that TGF-beta induces ET-1 in normal and fibrotic lung fibroblasts in a Smad-independent ALK5/c-Jun N-terminal kinase (JNK)/Ap-1-dependent fashion. ET-1 induces JNK through TAK1. Fibrotic lung fibroblasts display constitutive JNK activation, which was reduced by the dual ETA/ETB receptor inhibitor, bosentan, providing evidence of an autocrine endothelin loop. Thus, ET-1 and TGF-beta are likely to cooperate in the pathogenesis of pulmonary fibrosis. As elevated JNK activation in fibrotic lung fibroblasts contributes to the persistence of the myofibroblast phenotype in pulmonary fibrosis by promoting an autocrine ET-1 loop, targeting the ETA and ETB receptors or constitutive JNK activation by fibrotic lung fibroblasts is likely to be of benefit in combating chronic pulmonary fibrosis.

Actins↗
PubMed2003

The Ras/Raf/MEK/extracellular signal-regulated kinase pathway induces autocrine-paracrine growth inhibition via the leukemia inhibitory factor/JAK/STAT pathway.

Sustained activation of the Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) pathway can lead to cell cycle arrest in many cell types. We have found, with human medullary thyroid cancer (MTC) cells, that activated Ras or c-Raf-1 can induce growth arrest by producing and secreting an autocrine-paracrine factor. This protein was purified from cell culture medium conditioned by Raf-activated MTC cells and was identified by mass spectrometry as leukemia inhibitory factor (LIF). LIF expression upon Raf activation and subsequent activation of JAK-STAT3 was also observed in small cell lung carcinoma cells, suggesting that this autocrine-paracrine signaling may be a common response to Ras/Raf activation. LIF was sufficient to induce growth arrest and differentiation of MTC cells. This effect was mediated through the gp130/JAK/STAT3 pathway, since anti-gp130 blocking antibody or dominant-negative STAT3 blocked the effects of LIF. Thus, LIF expression provides a novel mechanism allowing Ras/Raf signaling to activate the JAK-STAT3 pathway. In addition to this cell-extrinsic growth inhibitory pathway, we find that the Ras/Raf/MEK/ERK pathway induces an intracellular growth inhibitory signal, independent of the LIF/JAK/STAT3 pathway. Therefore, activation of the Ras/Raf/MEK/ERK pathway can lead to growth arrest and differentiation via at least two different signaling pathways. This use of multiple pathways may be important for "fail-safe" induction and maintenance of cell cycle arrest.

Adenoviridae↗
PubMed1988

Expression of recombinant platelet-derived growth factor A- and B-chain homodimers in rat-1 cells and human fibroblasts reveals differences in protein processing and autocrine effects.

The autocrine effects of platelet-derived growth factor (PDGF) A- and B-chain homodimers (PDGF-AA and PDGF-BB) on rat-1 cells and human fibroblasts have been investigated by using human PDGF A- and B-chain cDNA clones expressed in a retroviral vector. Infection with replication-defective virus carrying the B-chain cDNA resulted in a phenotypical transformation resembling that induced by simian sarcoma virus. The resulting cells were focus forming in monolayer cultures, grew to high saturation densities, and formed large colonies in soft agar. The PDGF A-chain transfectants showed no transformed morphology and lacked focus-forming activity but grew to high saturation density in monolayer culture and formed small colonies in soft agar. A similar but weaker effect was obtained with an A-chain cDNA variant containing a 69-base-pair insertion in the 3' end of the protein-coding domain. A- and B-chain transfectants released PDGF receptor-competing activity into the medium, but only the medium conditioned by the B-chain transfectants possessed potent mitogenic activity on human fibroblasts. Both types of transfectants had downregulated levels of PDGF receptors; however, the B-chain transfectants were downregulated to significantly lower levels. Metabolic labeling and immunoprecipitations with PDGF antiserum showed that the PDGF B-chain protein was processed to a 24-kilodalton cell-associated and a 30-kilodalton secreted dimeric protein. The A-chain protein was rapidly secreted as a 31-kilodalton dimeric protein. The present study shows a marked difference in the autocrine effects of PDGF-AA and -BB expressed under the control of a retroviral promoter and suggests that different biological properties may be assigned to these two PDGF isoforms.

Animals↗