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PubMed2002

Heterotypic adhesion-induced mast cell activation: biologic relevance in the inflammatory context.

In addition to being a major effector cell in the elicitation of allergic inflammation, mast cells have been found to be activated in various T cell-mediated inflammatory processes and to reside in close physical proximity to T cells. Such observations have led investigators to propose a functional relationship between these two cell populations. In this regard, we have recently reported that murine and human mast cells can be activated to both release granule-associated mediators, such as histamine and matrix metalloproteinase-9 (MMP-9), and to produce several cytokines (i.e. TNF-alpha, IL-4 and IL-6) upon physical contact, which is adhesion molecule mediated, with activated T cells. This cascade of events, whereby mast cells are activated by T cells to release certain mediators which are known to be essential for leukocyte extravasation and recruitment to affected sites, points to an important immunoregulatory function of mast cells within the context of T cell-mediated inflammatory processes.

Autocrine Communication↗

PubMed2000

Paracrine and autocrine effects of nitric oxide on myocardial function.

Complex paracrine interactions exist between endothelial cells and cardiac myocytes in the heart. Cardiac endothelial cells release (or metabolize) several diffusible agents (e.g., nitric oxide [NO], endothelin-1, angiotensin II, adenylpurines) that exert direct effects on myocyte function, independent of changes in coronary flow. Some of these mediators are also generated by cardiac myocytes, often under pathological conditions. This review focuses on the role of NO in this paracrine/autocrine pathway. NO modulates several aspects of "physiological" myocardial function (e.g., excitation-contraction coupling; myocardial relaxation; diastolic function; the Frank-Starling response; heart rate; beta-adrenergic inotropic response; and myocardial energetics and substrate metabolism). The effects of NO are influenced by its cellular and enzymatic source, the amount generated, the presence of reactive oxygen species, interactions with neurohumoral and other stimuli, and the relative activation of cyclic GMP-dependent and -independent signal transduction pathways. The relative physiological importance of endothelium- and myocyte-derived NO remains to be established. In pathological situations (e.g., ischemia-reperfusion, left ventricular hypertrophy, heart failure, transplant vasculopathy and rejection, myocarditis), NO can potentially exert beneficial or deleterious effects. Beneficial effects of NO can result from endothelial-type nitric oxide synthase-derived NO or from spatially and temporally restricted expression of the inducible isoform, inducible-type nitric oxide synthase. Deleterious effects may result from (1) deficiency of NO or (2) excessive production, often inducible-type nitric oxide synthase-derived and usually with concurrent reactive oxygen species production and peroxynitrite formation. The balance between beneficial and deleterious effects of NO is of key importance with respect to its pathophysiological role.

Autocrine Communication↗

PubMed2001

Neurosteroids: recent findings.

The term neurosteroid applies to those steroids that are synthesized in the nervous system, from cholesterol or other blood-borne steroidal precursors, and that accumulate in the nervous system to levels that are at least in part independent from steroidogenic gland secretion. Both glial cells and neurons participate in neurosteroid biosynthesis and metabolism. Several neurosteroids are involved in auto/paracrine mechanisms involving regulation of target gene expression and/or effects on membrane receptors (particularly those for neurotransmitters). An additional unexpected mechanism of steroid action is reported here: pregnenolone binds to neural microtubule-associated protein of type 2 (MAP2) and increases both the rate and extent of tubulin polymerization, forming microtubules of normal electron microscopic appearance. This novel mechanism may play a role in regulating microtubule formation and dynamics and thus neuronal plasticity and function.

Animals↗

PubMed2001

Progesterone synthesis and myelin formation in peripheral nerves.

Progesterone is synthesized in the nervous system by neurons and glial cells. Because of their simple structure, plasticity and capacity of regeneration, peripheral nerves are particularly well suited for studying the biosynthesis, mechanisms of action and effects of the hormone. Schwann cells, the myelinating glial cells in the peripheral nervous system, synthesize progesterone in response to a diffusible neuronal signal. In peripheral nerves, the local synthesis of progesterone plays an important role in the formation of myelin sheaths. This has been shown in vivo, after cryolesion of the mouse sciatic nerve, and in vitro, in cocultures of Schwann cells and sensory neurons. Schwann cells also express an intracellular receptor for progesterone, which thus functions as an autocrine signalling molecule. Progesterone may promote myelination by activating the expression of genes coding for transcription factors (Krox-20) and/or for myelin proteins (P0, PMP22). Recently, it has been proposed that progesterone may indirectly regulate myelin formation by influencing gene expression in neurons. Steroid hormones also influence the proliferation of Schwann cells: estradiol becomes a potent mitogen for Schwann cells when levels of cAMP are elevated and glucocorticosteroids have been shown to increase the mitogenic effects of peptide growth factors.

Animals↗

PubMed1998

Paracrine regulation of human placenta: control of hormonogenesis.

There is much evidence indicating that the human placenta plays a very important role in modulating the endocrinology of pregnancy. Placental tissue produces cytokines, hormones and growth factors that are essential in the regulation of the feto-maternal unit. The production of these substances is regulated by a network of interactions within and between intra-uterine through paracrine and/or autocrine mechanisms. Communication between the gestational intra-uterine tissues is critical for successful pregnancy, from the earliest stage of implantation until the expulsive phase of delivery. This is confirmed by the demonstration that the human placenta directly controls the release of substances such as hCG, hPL, steroid hormones and prostaglandins. Furthermore, there is evidence that intra-uterine tissues also can regulate ACTH release and have effects on the hypothalamus-pituitary-gonadal axis and the hypothalamus-pituitary-adrenal axis. The set of data reported in this article confirms that the placenta must be considered an organ that is essential for the initiation, maintenance and successful conclusion of pregnancy and that an imbalance between the complex network of placental regulating systems may cause serious gestational disorders.

Adrenocorticotropic Hormone↗

PubMed1999

Autocrine B-cell stimulation by interleukin-2 during a cognate interaction with T-cells.

Interleukin-2 (IL-2) secretion as well as expression of IL-2 receptor has been demonstrated for B-cells in response to several activating stimuli. However, the exact role of B-cell-derived IL-2 in the T-cell-dependent antibody response remains to be determined. Here, we have examined the autocrine regulatory roles of IL-2 secreted from B-cells. Splenic resting B-cells were stimulated with a fixed pre-activated Th1 clone, G1.19, in the presence of a single amino acid-substituted peptide (pD129A; Ala-129 substituted for Asp-129), an analog of the original ligand (p119-133, derived from bovine beta-lactoglobulin) recognized by G1.19 cells. pD129A allowed a cognate interaction between B-cells and fixed pre-activated G1.19 T-cells, but pD129A had no agonistic activity against G1.19 T-cells. Thus, the level of expression of B-cell-activating molecules on T-cells remained unchanged after stimulation with pD129A. Regardless of the lack of ability to induce IL-2 secretion in the case of T-cells, pD129A significantly enhanced antibody secretion from B-cells, and this was partially blocked by anti-IL-2 antibody. Furthermore, IL-2 secretion from B-cells was modestly upregulated in response to added pD129A. Taken together, these data suggest that helper signals from interacting cognate T-cells induce IL-2 secretion by B-cells, which can enhance antibody secretion in an autocrine manner.

Animals↗

PubMed2001

Agonists of the retinoic acid- and retinoid X-receptors inhibit hepatocyte growth factor secretion and expression in U87 human astrocytoma cells.

Retinoids participate in the onset of differentiation, apoptosis and the inhibition of growth in a wide variety of normal and cancerous cells. Several recent reports have shown that hepatocyte growth factor (HGF), and its receptor, c-Met, are expressed at abnormally high levels in various human malignant gliomas and exert a strong proliferative action in an autocrine fashion. These results, consequently, imply that HGF and its receptor may represent a major contributor to the progression of such malignancies. Since astrocytomas are the most frequently occurring glioma, we have shown here that U87 cells - a well-established, human astrocytoma cell line - express both HGF and c-Met, thereby providing a suitable astrocytic tumor model for studying the potential role of HGF, functioning in an autocrine mode, in astrocytic tumorigenesis. Furthermore, we demonstrated the expression of the retinoic acid receptor (RAR) isoforms, RARalpha, -beta and -gamma, as well as the retinoid x-receptor (RxR) isoforms, RxRalpha and -beta, by RT-PCR and western blot analysis in these cells. Since ligands of the RARs and RxRs are known to exert growth inhibitory effects on various tumor cells which include some astrocytomas, we speculated that such effect of retinoids might be mediated via inhibition of HGF secretion in human astrocytoma cells. Indeed, we have shown that the RAR agonists, all-trans retinoic acid (ATRA) and (E)-4-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)-1-propenyl] benzoic acid (TTNPB), inhibited HGF secretion with half maximal inhibition occurring at 3.0 microM and 15 nM, respectively, as did the RxR agonists, 9-cis- and 13-cis retinoic acid (9cRA and 13cRA, respectively), which exerted half-maximal inhibitory effects at 40 and 25 nM, respectively. These actions of the RAR and RxR agonists appear to be exerted at the transcriptional level as assessed by Northern blot analysis. Taken together, our results show for the first time that retinoids, acting via the RAR and RxRs, significantly inhibit both the secretion and expression of HGF, thereby interrupting a potentially highly tumorigenic autocrine loop in astrocytoma cells.

Antineoplastic Agents↗

PubMed2001

Inflammatory gene transcription in human astrocytes exposed to hypoxia: roles of the nuclear factor-kappaB and autocrine stimulation.

Mechanisms of hypoxia-induced activation of nuclear factor-kappaB (NF-kappaB) and inflammatory genes were investigated in fetal human astrocytes in culture. Astrocytes were subjected to interleukin-1beta (IL-1beta; 50-100 u/ml; 4-24 h), or to a 4-h hypoxia (<2% O2) followed by a 4-24-h reoxygenation. NF-kappaB binding and transcriptional activity increased up to 10-fold in astrocytes exposed to IL-1beta, and up to 3-fold in astrocytes subjected to hypoxia followed by reoxygenation. Both IL-1beta- mRNAs and proteins hypoxia-induced NF-kappaB activation were blocked by the proteasome inhibitor, MG-132. MG-132 inhibited IL-1beta-induced up-regulation of IL-1beta and IL-8 mRNA and protein but increased hypoxia-stimulated expression/release of IL-1beta and IL-8. IL-1 receptor antagonist (IL-1Ra) blocked both hypoxic astrocyte-conditioned media-induced NF-kappaB activation and the expression/release of IL-1beta and IL-8. Astrocytes subjected to hypoxia in the presence of IL-1Ra failed to activate NF-kappaB, but expressed elevated levels of IL-1beta and IL-8. The data suggest that hypoxia/reoxygenation-induced up-regulation of IL-1beta and IL-8 in human astrocytes has two components, a NF-kappaB independent up-regulation during hypoxia, followed by amplification through autocrine IL-1beta-induced NF-kappaB activation during reoxygenation.

Astrocytes↗

PubMed2002

A non-peptide substance P antagonist down-regulates SP mRNA expression in human mononuclear phagocytes.

Substance P (SP), a potent modulator of neuroimmunoregulation, exerts its activity by binding to the neurokinin-1 receptor (NK-1R). The SP-NK-1R interaction is important in inflammation and viral infections, including HIV infection of human immune cells. We recently demonstrated that SP modulates HIV replication and that a non-peptide SP antagonist CP-96,345 inhibits HIV replication in human monocyte-derived macrophages (MDM) by affecting the SP-NK-1R interaction. In order to examine the effect of the SP antagonist on SP mRNA expression, MDM was incubated with or without CP-96,345 in the presence or absence of HIV infection. SP mRNA expression in these cells was then determined by real-time PCR technology. The effect of CP-96,345 on chemokine gene expression was also investigated by using a cDNA array assay. CP-96,345 down-regulated SP mRNA expression and antagonized exogenous SP-enhanced SP expression at the mRNA level, suggesting that SP autocrine regulation was interrupted by CP-96,345. CP-96,345 inhibited HIV replication in MDM, associated with down-regulated SP mRNA expression in comparison to HIV infection controls. In parallel with down-regulated SP and CCR5 mRNA expression, cDNA array assays indicated that CP-96,345 treatment also inhibited IL-8 gene expression, while enhancing expression of fractalkine and monocyte chemotactic protein-3 (MCP-3). Since SP plays an important role in inflammation and viral infections, these studies may have potential applications for therapeutic intervention of inflammation and viral infection of immune cells.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1998

Human lymphocytes express substance P and its receptor.

We present data demonstrating the gene expression of substance P (SP) and its receptor in human peripheral blood-isolated lymphocytes. Using reverse transcribed polymerase chain reaction (RT-PCR) assay, preprotachykinin-A (substance-P) mRNA is detected in human peripheral blood-isolated lymphocytes. Among the alpha, beta, and gamma transcripts of the SP gene, only the beta and gamma transcripts are detectable in these cells. These RT-PCR amplified transcripts are recognized by Southern blot assay using a specific SP probe. Direct DNA sequence analysis of the RT-PCR products from lymphocytes also confirmed the structure of these transcripts which are identical to those found in human neuronal cells. At the protein level, human lymphocytes produced endogenous SP as determined by an enzyme immunoassay. Capsaicin, a vanillyl fatty acid amide (ingredient of hot pepper), released preformed SP from lymphocytes. In addition, using RT/nested-PCR analysis, we identified the presence of mRNA for neurokinin-1 receptor (the receptor for SP) in human peripheral blood-isolated lymphocytes, which was confirmed by Southern blot and DNA sequencing analysis. The demonstration that human lymphocytes express SP and its receptor support the notion that SP is biologically involved in regulating the functions of these cells in an autocrine fashion.

Adult↗

PubMed1998

Cultured sympathetic neurons express functional interleukin-1 receptors.

Since recent work has identified an apoptotic pathway in sympathetic neurons that is mediated by autocrine interleukin-1 (IL-1), we investigated whether cultured sympathetic neurons possess functional IL-1 receptors. Cultured sympathetic neurons express levels of IL-1RI and IL-1RAcP mRNAs consistent with signal transduction. Neurons stimulated with IL-1 demonstrate enhanced p65 NF-kappaB nuclear translocation and enhanced NF-kappaB DNA binding activity, with at least p65 and p50 subunits participating in the DNA binding activity. RNA differential display identified several neuronal mRNAs regulated by IL-1, including a member of the reticulon family. We conclude that IL-1 stimulates a potential component of a neuronal secretory pathway.

Animals↗

PubMed1999

GABA(A) receptors mediate inhibition of T cell responses.

We describe the presence of functional GABA(A) receptors on T cells. GABA inhibited anti-CD3 and antigen-specific T cell proliferation in vitro in a dose-dependent manner that was 1) mimicked by the GABA(A) receptor agonist muscimol (but not the GABA(B) receptor agonist baclofen), 2) blocked by GABA(A) receptor antagonists and a GABA(A) receptor Cl- channel blocker (picrotoxin) and 3) enhanced by pentobarbital. These data suggest that GABA(A) receptors mediate this immune inhibition and that these receptors can be modulated in a similar fashion to their neuronal counterparts. Finally, GABA inhibited DTH responses in vivo. Thus, pharmacological modulation of GABA(A) receptors may provide new approaches to modulate T cell responses in inflammation and autoimmune disease.

Amidines↗

PubMed1999

Schwann cells and their precursors emerge as major regulators of nerve development.

It is becoming ever clearer that Schwann cells and Schwann-cell precursors are an important source of developmental signals in embryonic and neonatal nerves. This article reviews experiments showing that these signals regulate the survival and differentiation of other cells in early nerves. The evidence indicates that glial-derived signals are necessary for neuronal survival at crucial periods of development, that they regulate the molecular and functional specialization of axons and that they control the maturation of the perineurial sheath that protects nerves from inflammation and unwanted macro-molecules produced in the surrounding tissues. Furthermore, an autocrine survival circuit enables Schwann cells in postnatal nerves to survive in the absence of axons, a vital requirement for successful nerve regeneration following injury. The molecular identity of these signals and their receptors is currently being determined.

Animals↗

PubMed2002

Parathyroid hormone-related protein enhances PC-3 prostate cancer cell growth via both autocrine/paracrine and intracrine pathways.

Parathyroid hormone-related protein (PTHrP) is expressed by human prostatic tissue and prostate cancer cell lines, and positively influences primary prostate tumor growth in vivo. The human prostate cancer cell line PC-3, which expresses functional PTH/PTHrP receptors, was used as a model to study the effects of PTHrP on prostate cancer cell growth. Addition of PTHrP (1-34), (1-86), and (1-139) increased cell number and [3H]thymidine incorporation; these effects were reversed by anti-PTHrP antiserum. This antiserum also decreased endogenous PC-3 cell growth. Clonal PTHrP-overexpressing PC-3 cell lines also showed enhanced cell growth and [3H]thymidine incorporation and were enriched in the G2+M phase of the cell cycle, suggesting an effect of PTHrP on mitosis. Overexpression of PTHrP with the nuclear localization sequence (NLS) deletion partially reversed the growth-stimulatory effects. The growth rate of these cells was midway between that of wild-type PTHrP-overexpressing and control cells, presumably because NLS-mutated PTHrP is still secreted and acts through the cell surface PTH/PTHrP receptor. In contrast to NLS-mutated PTHrP, wild-type protein showed preferential nuclear localization. These results suggest that the proliferative effects of PTHrP in PC-3 cells are mediated via both autocrine/paracrine and intracrine pathways, and that controlling PTHrP production in prostate cancer may be therapeutically beneficial.

Autocrine Communication↗

PubMed2003

Adrenomedullin is an autocrine/paracrine growth factor for rat vascular smooth muscle cells.

Adrenomedullin is a potent vasodilator peptide secreted by vascular endothelial and smooth muscle cells. Adrenomedullin stimulates the proliferation of quiescent rat vascular smooth muscle cells (VSMCs) via p42/p44 ERK/MAP kinase activation. Recently, receptor-activity-modifying proteins (RAMPs) have been shown to transport calcitonin-receptor-like-receptor (CRLR) to the cell surface to present either as CGRP receptor or adrenomedullin receptor. We investigated whether adrenomedullin acts as an autocrine/paracrine growth factor for cultured rat VSMCs and whether coexpressions of RAMP isoform and CRLR may mediate p42/p44 ERK/MAP kinase activation by adrenomedullin. Adrenomedullin dose-dependently stimulated the proliferation of quiescent rat VSMCs, and this effect was inhibited by an adrenomedullin receptor antagonist, a MAP kinase kinase inhibitor and phosphatidylinositol 3-kinase inhibitors. Addition of either CGRP(8-37) or anti-adrenomedullin antibody to exponentially growing rat VSMCs inhibited the serum-induced cell proliferation, suggesting its role as an autocrine/paracrine growth factor. Cotransfection of RAMP2 or RAMP3 with CRLR into rat VSMCs potentiated activation of cAMP activity, but not of p42/p44 ERK/MAP kinase activity in response to adrenomedullin. Our results suggest that adrenomedullin is an autocrine/paracrine growth factor for rat VSMCs via p42/p44 ERK/MAP kinase and phosphatidylinositol 3-kinase pathways and that it is not mediated by human RAMP-CRLR receptors.

Adrenomedullin↗

PubMed1997

Human neuroblastoma cells use either insulin-like growth factor-I or insulin-like growth factor-II in an autocrine pathway via the IGF-I receptor: variability of IGF, IGF binding protein (IGFBP) and IGF receptor gene expression and IGF and IGFBP secretion in human neuroblastoma cells in relation to cellular proliferation.

Neuroblastoma cells are thought to depend upon autocrine stimulation by IGF-II but not by IGF-I. We have studied the expression of IGF, IGFBP and IGF receptor mRNA in two human neuroblastoma cell lines, SK-N-MC and CHP, and asked whether or not the expression of the IGF system in these malignant cells determines their growth pattern. SK-N-MC cells grow with a cell doubling time of 36 hours in medium supplemented with 10% fetal calf serum whereas CHP cells only grow with a doubling time of 72 h. In addition, the SK-N-MC cell line has a plating efficiency ten times greater than the CHP cell line. RNase protection assays were performed using (32)P-labelled riboprobes and RNA that had been purified from SK-N-MC and CHP cells respectively. A 520 bases human IGF-I, a 556 bases human IGF-II, a 480 bases human IGF-I receptor and a 250 human IGF-II/mannose-6-phosphate (M6P) receptor probe were radiolabelled as were human IGFBP-1, -2, -3, -4, -5 and -6 probes. While both SKNMC and CHP neuroblastoma cells expressed mRNAs for IGFBP-2, -4, and -6 no signal was detected for IGFBP-1, and -3 and only SK-N-MC cells expressed IGFBP-5 mRNA. In addition, a 400 bases protected band was seen with the IGF-I receptor probe and a 260 bases protected band with the IGF-IIM6P receptor probe in either cell line. Interestingly, a 300 bases protected species was detected with the IGF-II probe in CHP cell RNA whereas SK-N-MC cells did not express IGF-II transcripts. Conversely, SK-N-MC cells expressed a 520 bases IGF-I transcript while CHP cells did not show IGF-I mRNA expression. As determined by specific radioimmunoassays SK-N-MC cells secreted 0.75+/-0.02 ng/ml IGF-I, 1.2+/-0.04 ng/ml IGF-II and 149+/-2.1 ng/ml IGFBP-2 within 24 h, whereas CHP cells secreted 0.1+/-0.01 ng/ml IGF-I, but 6.2+/-0.1ng/ml IGF-II and 254.8+/-5.5 ng/ml IGFBP-2 (N=5). IGFBP-2 secretion correlated positively with IGF-II secretion in CHP cells (r=0.85, P=0.05) and negatively with IGF-I (r= -0.9, P<0.01) in SK-N-MC cells. In conclusion, SK-N-MC cells which grow rapidly and have a high plating efficiency, express IGF-I, while CHP cells that grow more slowly express IGF-II. We hypothesize that neuroblastoma cells depend upon autocrine stimulation by either IGF-I or IGF-II. Variable sensitivity to growth inhibitors or apoptotic processes may be related to the differential expression of the IGF system.

Autocrine Communication↗

PubMed1999

The v-Myb oncoprotein activates C/EBPbeta expression by stimulating an autoregulatory loop at the C/EBPbeta promoter.

Previous studies have implicated the CCAAT box/enhancer binding protein beta (C/EBPbeta) in the regulation of cell-type specific gene expression in myelomonocytic cells and in the activation of target genes by the transcription factor v-Myb. To better understand the role of C/EBPbeta in myelomonocytic cells we have cloned the chicken C/EBPbeta gene and studied its regulation. The chicken C/EBPbeta promoter contains a number of C/EBP binding sites and is activated by C/EBPbeta, suggesting that the C/EBPbeta gene is autoregulated by its own protein product. Interestingly, the C/EBPbeta promoter is not activated by C/EBPalpha, another C/EBP family member highly expressed in myelomonocytic cells, indicating that the autoregulation is specific for C/EBPbeta. Comparison of different C/EBP inducible promoters shows that the relative transactivation potential of C/EBPalpha and beta is extremely dependent on the promoter context. By using the promoters of the mim-1 and C/EBPbeta genes and by exchanging the DNA-binding domains between C/EBPalpha and beta we show that the observed promoter preferences of C/EBPalpha and beta are not due to differential DNA-binding but instead depend on the transactivation domains of these proteins. The C/EBPbeta promoter also contains several Myb binding motifs, suggesting that the C/EBPbeta gene is also myb-inducible. We show that the C/EBPbeta promoter is activated synergistically by v-Myb and C/EBPbeta and that transcription of the endogenous C/EBPbeta gene is increased by v-Myb. Thus, our results identify the C/EBPbeta gene as a novel v-Myb target gene. Taken together, our data suggest a model for the regulation of C/EBPbeta expression in which v-Myb stimulates the synthesis of C/EBPbeta by enhancing an autoregulatory loop acting on the C/EBPbeta promoter.

Animals↗

PubMed1998

Production and oestrogen regulation of FGF1 in normal and cancer breast cells.

To investigate the relationship between the FGF1 oestrogen regulation and the normal/cancer status of breast cells, we have studied FGF1 17beta-oestradiol regulation in normal, transformed and cancerous cells. Normal (NMEC), transformed (HBL-100) and cancerous (MCF-7, MDA-MB-231) human mammary epithelial cells express different levels of FGF1 mRNAs. Western blot analysis allowed us to characterize FGF1 as an 18 kDa form of this polypeptide. Using a neutralizing anti-FGF1 antibody we demonstrated that FGF1 is secreted by all mammary cells studied and stimulates their proliferation in an autocrine manner. We have examined the regulation of FGF1 mRNAs in response to 17beta-oestradiol. FGF1 mRNAs were upregulated in hormone-dependent NMEC but was not upregulated either in hormone-sensitive HBL-100 cells or in the hormone-dependent cancerous cell line MCF-7. However, enzyme linked immunosorbent assay indicated an increase of FGF1 protein in NMEC, HBL-100 and MCF-7 cells. We have also examined the 17beta-oestradiol regulation of the four alternatively spliced FGF1 mRNAs: 1.A, 1.B, 1. C and 1.D. Only 1.B transcripts were downregulated by 17beta-oestradiol in normal cells. These results show that 17beta-oestradiol regulates FGF1 mRNAs in a cell-specific manner, and that this regulation may be transcriptional or translational depending on cell phenotype. The specificity of oestradiol effects was checked using its receptor antagonist tamoxifen.

Alternative Splicing↗