Showing papers by "Michael B. Sporn published in 1992"
TL;DR: There has been immense progress in TGF-/~ research in the past two years and this mini-review will highlight some of these accomplishraents and indicate a few challenges for the future.
Abstract: I T is just 10 years since the peptide, transforming growth factor-/31 (TGF-~I) 1, was isolated from human platelets, human placenta, and bovine kidney and characterized as a discrete molecular entity, namely a 25-kD homodimer with a unique NH2-terminal sequence. Two years later this molecule was cloned, and subsequently four other closely related isoforms have been found in vertebrates; three isoforms (TGF-~s 1, 2, and 3) are known in man. TGF-~ can now be considered the prototype of a multifunctional cytokine, especially after the discovery that it could act both as an inhibitor and stimulator of cell replication, as well as control the synthesis of many of the components of the extracellular matrix (for reviews of the above see Roberts and Sporn, 1990; Massagu6, 1990; Moses et al., 1990; Sporn and Roberts, 1990). There has been immense progress in TGF-/~ research in the past two years. This mini-review will highlight some of these accomplishraents and indicate a few challenges for the future. We will confine this brief review to the TGF-/3s themselves and will not consider the extended TGF-B family, which includes the inhibins, activins, bone morphogenetic proteins, and related morphogenetic peptides, all of which are of increasing importance in many areas of cell biology, such as reproduction and development.
768 citations
TL;DR: It is found that modulator cells from animals orally tolerized to MBP produce a suppressor factor upon stimulation with MBP in vitro that is specifically inhibited by anti-transforming growth factor beta (TGF-beta) neutralizing antibodies.
Abstract: Oral administration of myelin basic protein (MBP) is an effective way of suppressing experimental autoimmune encephalomyelitis (EAE). We have previously shown that such suppression is mediated by CD8+ T cells, which adoptively transfer protection and suppress immune responses in vitro. In the present study we have found that modulator cells from animals orally tolerized to MBP produce a suppressor factor upon stimulation with MBP in vitro that is specifically inhibited by anti-transforming growth factor beta (TGF-beta) neutralizing antibodies. No effect was observed with antibodies to gamma interferon, tumor necrosis factor alpha/beta, or indomethacin. In addition, the active form of the type 1 isoform of TGF-beta 1 (TGF-beta 1) can be directly demonstrated in the supernatants of cells from animals orally tolerized to MBP or ovalbumin after antigen stimulation in vitro. Antiserum specific for TGF-beta 1 administered in vivo abrogated the protective effect of oral tolerization to MBP in EAE. Furthermore, injection of anti-TGF-beta 1 serum to nontolerized EAE animals resulted in an increase in severity and duration of disease. These results suggest that immunomodulation of EAE induced by oral tolerization to MBP and natural recovery mechanisms use a common immunoregulatory pathway that is dependent on TGF-beta 1. Implications of such an association are of therapeutic relevance to human autoimmune diseases and may help to explain one of the mechanisms involved in the mediation of active suppression by T cells.
725 citations
TL;DR: Of all of the growth factors, none has been found to have the diversity of effects on ECM ascribed to transforming growth factor-β (TGF-β).
470 citations
Journal Article•
TL;DR: In vivo evidence is found that 3 months of tamoxifen treatment causes a consistent induction of extracellular TGF-beta 1 in breast cancer biopsies, compared with matched pretreatment samples from the same patient.
Abstract: We have investigated the ability of tamoxifen to regulate members of the transforming growth factor beta (TGF-beta) family in human breast cancers in vivo. Using immunohistochemical techniques, we find that 3 months of tamoxifen treatment causes a consistent induction of extracellular TGF-beta 1 in breast cancer biopsies, compared with matched pretreatment samples from the same patient. The induced TGF-beta is localized between and around stromal fibroblasts and appears to be derived from these cells. Lower levels of TGF-beta 1,-beta 2, and -beta 3 seen in epithelial cells were not altered by tamoxifen treatment. The increased stromal staining of TGF-beta 1 occurred in estrogen receptor-negative as well as estrogen receptor-positive tumors. These results provide in vivo evidence for a novel, estrogen receptor-independent mechanism of action for tamoxifen, involving the stromal induction of a potent growth inhibitor for epithelial cells.
366 citations
TL;DR: A role is suggested for TGF beta 1, not only in inflammation, but also in the tissue-specific glial scar formation that occurs in the CNS to help limit the pathogenesis associated with matrix deposition in the wound.
235 citations
TL;DR: Recent characterization of the 5′ regulatory regions of the human TGF‐β 1, 2, and 3 genes suggests that distinct features of the promoters, including the presence of TATAA boxes and transcription factor binding sites, form the basis for the observed differential transcription.
Abstract: The TGF-beta's are multifunctional, pleiotropic molecules with major effects in control of cellular migration, cellular proliferation, and elaboration of extracellular matrix. Thus far, five distinct isoforms of TGF-beta have been described, each approximately 65-85% homologous and containing the characteristic 9 positionally conserved cysteine residues. Although the actions of the activated mature forms of the different isoforms on cells are qualitatively similar in most cases, there are a few examples of distinct activities. For example, TGF-beta's 1 and 3, but not TGF-beta 2, inhibit the growth of large vessel endothelial cells, and TGF-beta's 2 and 3, but not TGF-beta 1, inhibit the survival of cultured embryonic chick ciliary ganglionic neurons. In addition, selective targeting of the latent forms of the TGF-beta's is suggested by the observation that latent TGF-beta 2 is the prominent isoform found in body fluids such as amniotic fluid, breast milk, and the aqueous and vitreous humor of the eye; it is noteworthy in this regard that TGF-beta 2 is unique among various isoforms in that it lacks a RGD integrin-binding sequence in its precursor. The most dramatic differences in the TGF-beta isoforms are seen at the level of expression, where there is now a wealth of data demonstrating both spatially and temporally distinct expression of both the mRNAs and proteins in developing tissues, regenerating tissues, and in pathologic responses.(ABSTRACT TRUNCATED AT 250 WORDS)
181 citations
TL;DR: The results suggest that the type II receptor is necessary for mediating the effects of TGF-beta on inhibition of growth but not on gene activation of the hybrid cells.
171 citations
TL;DR: Computer analysis showed that this region of the 5'-UTR contained a stable secondary stem-loop structure alone is sufficient to inhibit expression of the growth hormone gene, suggesting that it plays an important role in post-transcriptional regulation of TGF-beta 1 gene expression.
170 citations
TL;DR: The concept of autocrine secretion, its subsequent modifications, its application for understanding pathogenesis of disease, and its potential for developing new approaches to prevention and treatment are reviewed.
Abstract: The concept of autocrine secretion, its subsequent modifications, its application for understanding pathogenesis of disease, and its potential for developing new approaches to prevention and treatment are reviewed. Peptide growth factors (cytokines) act as local autocrine and paracrine mediators of tissue homeostasis. Many diseases, including cancer, atherosclerosis, rheumatoid arthritis, and other fibrotic diseases characterized by chronic inflammation, are associated with aberrant expression and cellular coordination of the homeostatic action of these regulatory molecules. Modern biotechnology and pharmacology offer unique opportunities for the therapeutic prevention and treatment of these molecular and cellular lesions, using either cytokines or other agents that modify their synthesis and activity.
169 citations
TL;DR: It is shown that transforming growth factor-beta and IL-1 beta also have antagonistic effects on the secretion of nitric oxide (NO) by these myocytes, and that NO secretion, the activity of NO synthase (NOS), and expression of the inducible form of NOS correlate inversely with the effects of these two agents on the beating rate.
Abstract: We have recently shown that transforming growth factor-beta (TGF beta) acts in an autocrine manner to maintain the beating rate of neonatal rat cardiac myocytes cultured in serum-free medium on cardiac fibroblast matrix. Interleukin-1 beta (IL-1 beta) suppresses the myocyte-beating rate, and TGF beta antagonizes this effect. We now show that TGF beta and IL-1 beta also have antagonistic effects on the secretion of nitric oxide (NO) by these myocytes, and that NO secretion, the activity of NO synthase (NOS), and expression of the inducible form of NOS correlate inversely with the effects of these two agents on the beating rate. Western blot analysis shows that treatment of myocytes with TGF beta antagonizes the induction of NOS after treatment with IL-1 beta. Release of NO, induced by IL-1 beta, is dependent upon the availability of the substrate, L-arginine, and is suppressed by a competitive inhibitor, NG-monomethyl-L-arginine. L-Arginine (> 0.25 mM) also suppresses, and NG-monomethyl-L-arginine (> 0.5 m...
146 citations
TL;DR: Findings provide direct evidence for a role of endogenous TGF-beta in the remissions seen in chronic relapsing EAE.
Abstract: Experimental allergic encephalomyelitis (EAE) is an autoimmune disease characterized by inflammation and demyelination in the central nervous system (CNS). Administration of transforming growth factor-beta (TGF-beta) has been shown to inhibit EAE. In this study, the possible role of endogenous TGF-beta in the regulation of relapsing EAE produced by the transfer of myelin basic protein-specific T cell lines was assessed. Although TGF-beta is not present in the normal CNS, this cytokine was detected by immunohistology in areas of central nervous system inflammation in both acute and chronic disease. The administration of anti-TGF-beta at the disease onset led to a worsening of the clinical course of EAE and more extensive pathological lesions. These findings provide direct evidence for a role of endogenous TGF-beta in the remissions seen in chronic relapsing EAE.
TL;DR: Altered expression of TGF-beta s 1, 2, and 3 at the protein level in mammary epithelia appears not to be a major feature of most breast lesions, raising the possibility that altered cellular response to the T GF-beta already present may play a role in the development of breast disease.
TL;DR: It is reported that exogenous TGF-beta stabilizes the beating rate of neonatal rat cardiac myocytes cultured on fibroblast matrix, and sustains their spontaneous rhythmic beating in serum-free medium, and it is shown that endogenous T GF-beta secreted by these myocytes acts in an autocrine fashion to maintain their beating rate.
Abstract: The three isoforms of transforming growth factor-beta (TGF-beta) have previously been implicated in embryonic development of the heart as well as in repair of myocardial damage after ischemia/reperfusion injury. TGF-beta 1 has also been localized intracellularly to both mitochondria and contractile filaments of cardiac myocytes, although its role in these structures has not been defined. We now report that exogenous TGF-beta stabilizes the beating rate of neonatal rat cardiac myocytes cultured on fibroblast matrix, and sustains their spontaneous rhythmic beating in serum-free medium. Moreover, using blocking antibodies to TGF-beta, we show that endogenous TGF-beta secreted by these myocytes acts in an autocrine fashion to maintain their beating rate. In contrast, IL-1 beta, an inflammatory mediator secreted by immune cells during myocardial injury, inhibits the beating of cardiac myocytes, and TGF-beta can overcome this inhibition. The antagonistic effects of TGF-beta and IL-1 were not observed when the myocytes were cultured on gelatin, as compared to native fibroblast matrix. The data indicate that TGF-beta is an important regulator of contractile function of the heart and have significant implications for understanding cardiac physiology in health and disease.
TL;DR: These studies identify multiple transcription initiation sites for TGF-beta 2 and demonstrate that transcription from one of these promoters is dependent upon an ATF binding site located 5' of the TATA box.
TL;DR: The results identify the sequence between amino acids 40-82 as an important region within TGF-beta that functions to specify a T GF-beta 1- or TGF -beta 2-like activity.
Abstract: A chimeric transforming growth factor beta (TGF-beta) molecule has been synthesized to map the amino acids responsible for the substantially greater activity of TGF-beta 1 than TGF-beta 2 on growth and migration of endothelial cells. This chimera consists of a dimer of a monomeric unit composed of amino acids 1-39 of TGF-beta 2, 40-82 of TGF-beta 1, and 83-112 of TGF-beta 2. Structural identity of the purified recombinant protein has been confirmed by immunoblotting and NH2-terminal sequencing. The biological potency of the TGF-beta 2-1-2 chimera was equal to that of TGF-beta 1 in inhibition of growth of both fetal bovine heart endothelial cells and rat epididymal fat pad microvascular endothelial cells. Similarly, the TGF-beta 2-1-2 chimera was nearly equivalent to TGF-beta 1 and at least 10-fold more active than TGF-beta 2 in inhibiting migration of bovine aortic endothelial cells. These results identify the sequence between amino acids 40-82 as an important region within TGF-beta that functions to specify a TGF-beta 1- or TGF-beta 2-like activity.
TL;DR: A complex pattern of regulation of the different TGF‐β genes by themselves as well as by PDGF, EGF, IL‐1, dexamethasone, TPA, and retinoic acid in chicken embryo cells is indicated.
Abstract: Transforming growth factor-beta (TGF-beta) autoregulates its expression in several mammalian cell types. We now report that addition of TGF-beta s 1, 2, and 3 to primary chicken embryo cells differentially affects expression of the messenger RNAs for the different TGF-beta isoforms depending on the cell type. In cultured sternal chondrocytes, addition of TGF-beta s 1, 2, or 3 results in an increase in the steady-state levels of the messenger RNAs for TGF-beta s 2 and 3, but does not change expression of TGF-beta 4 mRNA. In contrast, in cultured cardiac myocytes, addition of TGF-beta s 1, 2, or 3 results in an increase in expression of TGF-beta s 3 and 4 mRNAs, but does not change expression of TGF-beta 2 mRNA. Moreover, expression of TGF-beta s 2, 3, and 4 mRNAs is not affected by addition of any of the TGF-beta s to fibroblasts. Addition of platelet-derived growth factor (PDGF), epidermal growth factor (EGF), or interleukin-1 (IL-1) to these chicken cells also has differential effects on expression of the different TGF-beta mRNAs depending on the cell type. Retinoic acid also has contrasting effects on chondrocytes and myocytes either increasing or decreasing, respectively, expression of TGF-beta s 2 and 3 mRNAs and TGF-beta 2 protein. Our results indicate a complex pattern of regulation of the different TGF-beta genes by themselves as well as by PDGF, EGF, IL-1, dexamethasone, TPA, and retinoic acid in chicken embryo cells.
TL;DR: The results suggest that TGF‐β4 may play an important role in the development of many tissues in the chicken, and expression being highest in smooth muscle and lowest in the kidney.
Abstract: Expression of TGF-beta 4 mRNA and protein was studied in the developing chicken embryo using specific cDNA probes and antibodies for chicken TGF-beta 4. Expression of TGF-beta 4 mRNA was detected by day 4 of incubation (Hamburger and Hamilton stage 22, E4) by RNA Northern blot analysis and increased with developmental age until day 12 of incubation (stage 38, E12) where it was detected in every embryonic tissue examined, with expression being highest in smooth muscle and lowest in the kidney. The steady-state level of expression of TGF-beta 4 mRNA remained relatively constant in most embryonic tissues through day 19 (stage 45, E19). In situ hybridization analysis detected TGF-beta 4 mRNA as early as the "definitive primitive streak" stage (stage 4); during neurulation (stage 10), TGF-beta 4 mRNA was detected in all three germ layers, including neuroectoderm. Following neurulation, TGF-beta 4 mRNA was detected in the neural tube, notochord, ectoderm, endoderm, sclerotome, and myotome, but not dermotome at stage 16. By day 6 of incubation (stage 29, E6), TGF-beta 4 mRNA was localized in several tissues including heart, lung, and gizzard. Immunohistochemical staining analysis also showed expression of TGF-beta 4 protein in all three germ layers as early as stage 4 in various cell types in qualitatively similar locations as TGF-beta 4 mRNA. These results suggest that TGF-beta 4 may play an important role in the development of many tissues in the chicken.
TL;DR: The effect of three different isoforms of transforming growth factor-β (TGF-β) on the expression of TGF- β2 mRNA was studied in several continuous tumor cell lines and a similar 2–3 fold increase in the level of secreted T GF-β2 was observed following treatment of A549 cells.
Abstract: The effect of three different isoforms of transforming growth factor-beta (TGF-beta) on the expression of TGF-beta 2 mRNA was studied in several continuous tumor cell lines. As previously reported for the mouse fibroblast cell line AKR-2B, the expression of TGF-beta 2 mRNA transcripts of 5.4, 4.7, 3.7 and 3.0 kb was decreased after a 24 hr treatment with 5 ng/ml of TGF-beta 1, TGF-beta 2 or TGF-beta 3. In A549, HBL-100 and BSC-1 epithelial cell lines, five distinct TGF-beta 2 mRNA transcripts of 5.8, 5.1, 4.0, 3.8 and 2.8 kb were detected by Northern blot analysis. Treatment of these cells with TGF-beta 1, TGF-beta 2 or TGF-beta 3 for 24 hr resulted in a 2-3 fold increase in the 5.8, 4.0 and 3.8 kb transcripts, with little detectable change in abundance of the 5.1 and 2.8 kb transcripts. The effect of the TGF-beta proteins was dose (5 ng/ml) and time (3-6 hr) dependent. A similar 2-3 fold increase in the level of secreted TGF-beta 2 was observed following treatment of A549 cells with TGF-beta 1. Basal level and induced expression of TGF-beta 2 mRNA in response to TGF-beta isoforms was decreased in the presence of actinomycin D. In all cell lines studied, the expression of the 2.5 kb TGF-beta 1 mRNA was relatively unchanged or markedly increased in response to treatment with TGF-beta.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: The SRE plays a critical role in the suppression of c-fos transcription by RA, which differentially inhibited proto-oncogene induction by mitogens, such as phorbol 12-myristate 13-acetate and serum.
TL;DR: The results indicate a complex pattern of transcriptional regulation of the chicken TGF-beta 3 gene and suggest that differences in the regulation of expression of the genes for mammalian and avian TGF -beta 3 may result in part from the unique structure of their 5'-flanking regions.
Abstract: The promoter regions of the three mammalian transforming growth factor-beta genes (TGF-beta s 1, 2, and 3) have been recently cloned and characterized. The sequences show little similarity, suggesting different mechanisms of transcriptional control of these genes. To study differences in transcriptional regulation of mammalian and avian TGF-beta, we have cloned and sequenced the 5'-flanking region of chicken TGF-beta 3. Characterization of this region showed a TATA box and cAMP-responsive element (CRE) and AP-2 binding site consensus sequences starting at 12 and 28 base pairs, respectively, upstream from the TATA box. Moreover, four additional AP-2-like sites, 10 binding sites for the transcription factor Sp1, as well as two AP-1-like sites were also identified. Except for 32 base pairs of identity centered around the TATA box and CRE site and four other relatively small regions of identity, the chicken TGF-beta 3 promoter was found to be structurally very different from the human TGF-beta 3 promoter. Pro...
01 Jan 1992
TL;DR: The conventional clinical approach with most epithelial cancer has been to wait until the patient has invasive disease and then treat this disease with cytotoxic chemotherapy, surgery, or radiation; none of these modalities has been uniquely successful for the treatment of all types of epithelialcancer.
Abstract: Several years ago, we suggested that some new approaches are necessary if we intend to solve the problem of epithelial cancer in humans [1]. The conventional clinical approach that has been followed with most epithelial cancer has been to wait until the patient has invasive disease and then treat this disease with cytotoxic chemotherapy, surgery, or radiation. None of these modalities has been uniquely successful for the treatment of all types of epithelial cancer, in spite of some advances that have occurred. In the conventional approach to the disease, cancer is treated as if it were an entity that could be destroyed or removed, ignoring the evidence that cancer is a diffuse, evolutionary, developmental process [2]. What is called “cancer” in clinical incidence statistics is the process in its terminal stages; by this time many of the physiological controls that allow for orderly epithelial growth have been lost.
TL;DR: Results show that TGF-β1 and β2 peptides are detectable as early as the second week of human development.
Abstract: Using inununohistochemical methods we have investigated the presence of transforming growth factors β1, β2 and β1 precursor in a two-week-old trilaminar human embryo. TGF-β1 precursor was seen in both the epiblast and the hypoblast. In contrast to the widespread localization of TGF-β1 precursor in the embryo proper, antibodies to the mature TGF-β1 peptide localized preferentially to the hypoblast with only weak staining in the epiblast. Staining with antibodies to TGF-β2 was generally weak in both the epiblast and hypoblast layers of the embryo proper. These results show that TGF-β1 and β2 peptides are detectable as early as the second week of human development.
Book•
01 Jan 1992
TL;DR: Concepts of Preneoplasia for the Goal of Cancer Prevention and Prospects for the Chemoprevention of Breast Cancer are presented.
Abstract: Concepts of Preneoplasia for the Goal of Cancer Prevention- Steroids, Retinoids, and their Mode of Action- Epidermal Growth Factor, Glucocorticoid Hormones and Prolactin Act Sequentially in the Induction of Milk Protein Gene Expression- Interactions of Retinoids and Transforming Growth Factor-Beta in the Chemoprevention of Cancer- Growth Regulatory Networks in the Prostate- Prospects for the Chemoprevention of Breast Cancer