Showing papers by "Michael B. Sporn published in 1994"
Book•
01 Jan 1994
TL;DR: Retinoids In Photosensitive Systems John C. Saari Introduction / Overview of the Visual Process / Chromophores of Visual Pigments /photoisomerisation / Wavelength Regulation The Visual Cycle /Cellular Uptake of Retinol.
Abstract: lntroduction Michael B. Sporn and Anita B. Roberts The Synthetic Chemistry of Retinoids Marcia I. Dawson and Peter D. Hobbs Retinoid Skeletal-Bond Methodology / Methodology for Constructing the Polar Terminus of the Retinoid Skeleton Retinoids Specifically Designed to Aid Biologic Studies. Analytical Methods Harold C. Furr, Arun B. Barua, and James Allen Olson Biologic Samples / Reference Standards / Separation Methods Other Methods. Vitamin A In Human Nutrition: Public Health Considerations Barbara A. Underwood Historical Perspectives / Magnitude of the Problem of Vitamin A Deficiency Globally / Extraocular Health Consequences of Subclinical Deficiency / Assessment of Vitamin A Status. Retinol and Retinoic Acid Metabolism William S. Blaner and James Allen Olson Intestinal Uptake and Metabolism of Retinol / Hepatic Metabolism and Storage of Retinol / Uptake, Storage, and Metabolism of Retinol by Extrahepatic Tissues / Retinoic Acid Uptake and Formation / Metabolism of Retinoic Acid / Other Metabolites of Retinol. Plasma Retinol-Binding Protein Dianne Robert Soprano and William S. Blaner Retinol-Binding Protein Structure and Physiochemical Properties / The Molecular Biology of Retinol-Binding Protein / The Expression of Retinol-Binding Protein in the Liver and Extrahepatic Tissues / The Cellular Synthesis and Secretion of Retinol-Binding Protein and Its Regulation / Retinol Delivery to Cells by Retinol-Binding Protein / Clinical Studies and Possible Involvement of Retinol-Binding Protein in Disease. Cellular Retinoid-Binding Proteins David E. Ong, Marcia E. Newcomer, and Frank Chytil Discovery, Initial Characterization and Distribution of the Cellular-Retinoid Binding Proteins / Physical Properties of the Cellular-Retinoid Binding Proteins / Gene Structure and Regulation of Expression / Functions. The Retinoid Receptors David J. Mangelsdorf, Kazuhiko Umesono, and Ronald M. Evans Retinoid Receptors / A New Hormone: 9-cis-Retinoic Acid / Target-Gene Specificity / The Retinoid X Receptor Heterodimer: Master Regulator of Hormonal Signalling / Cross-Coupling in Retinoid Signalling Pathways / Retinoic Acid Receptor and Retinoid X Receptor Pattems of Expression / Human Disease. Retinoids In Photosensitive Systems John C. Saari Introduction / Overview of the Visual Process / Chromophores of Visual Pigments /photoisomerisation / Wavelength Regulation The Visual Cycle /Cellular Uptake of Retinol. Retinoids In Development Clementine Hofmann and Gregor Eichele Retinoids and Limb Development / Retinoids and the Pattern Along the Anteroposterior Body Axis / Effects of Retinoids on the Regenerating Amphibian Limb. Cellular Biology and Biochemistry of the Retinoids Lorraine J. Gudas, Michael B. Sporn, and Anita B. Roberts Overview of Mechanisms of Gene Regulation by Retinoids/ Effects of Retinoids on the Activity and Synthesis of Growth Factors and Their Receptors / Effects of Retinoids on the Activity and
1,369 citations
TL;DR: An important role is suggested for maternal sources of TGF-beta 1 during development and, more generally, evidence for maternal rescue of targeted gene disruption in the fetus is provided.
Abstract: Maternal sources of transforming growth factor-beta 1 (TGF-beta 1) are shown here to contribute to the normal appearance and perinatal survival of TGF-beta 1 null newborn mice. Labeled TGF-beta 1 crossed the placenta and was recovered intact from various tissues after oral administration to mouse pups. TGF beta-1 protein was also detected in cells recovered from breast milk. In immunohistochemical analyses, TGF-beta 1 null embryos and null newborn pups born to TGF-beta 1 heterozygotes stained positive for TGF-beta 1, whereas those born to a null female were negative and had severe cardiac abnormalities. These results suggest an important role for maternal sources of TGF-beta 1 during development and, more generally, provide evidence for maternal rescue of targeted gene disruption in the fetus.
508 citations
TL;DR: The results suggest that one of the possible mechanisms of escape from autocrine or paracrine growth control by TGF-beta during carcinogenesis could involve genetic changes in the T GF-beta type II receptor gene itself or altered expression of its mRNA.
Abstract: We have found several genetic changes in the TGF-beta-type II receptor gene in human gastric cancer cell lines resistant to the growth inhibitory effect of TGF-beta. Southern blot analysis showed deletion of the type II receptor gene in two of eight cell lines and amplification in another two lines. The single cell line we studied that is sensitive to growth inhibition by TGF-beta showed no structural abnormalities of the type II receptor gene. Some of the gastric cancer cells resistant to the growth inhibitory effect of TGF-beta express either truncated or no detectable TGF-beta type II receptor mRNAs, whereas the one that retains responsiveness to the growth inhibitory effect of TGF-beta expresses a full-size type II receptor mRNA. Immunoprecipitation followed by Western blot analysis showed parallel changes in TGF-beta type II receptor expression. Our results suggest that one of the possible mechanisms of escape from autocrine or paracrine growth control by TGF-beta during carcinogenesis could involve genetic changes in the TGF-beta type II receptor gene itself or altered expression of its mRNA.
424 citations
TL;DR: It is demonstrated that transforming growth factor β1 participates in the scarring response in the rat brain, and the potential use for TGFβ1 antagonists as inhibitors of scar formation in the injured mammalian CNS is self‐evident.
Abstract: In the central nervous system (CNS), nerve regeneration after traumatic injury fails. The formation of a dense fibrous scar is thought to restrict in part the growth of axonal projections, providing one of the many reasons that complete lesions of neural pathways in the adult mammalian CNS are rarely followed by significant functional recovery. In order to determine which mechanisms mediate scar formation in the CNS and to investigate whether they can be modulated in vivo, we have attempted to define the potential role of trophic factors. Our previous studies have shown the focal elevation of transforming growth factor beta 1 (TGF beta 1) expression in lesioned CNS tissue. In the studies described here, we demonstrate that TGF beta 1 participates in the scarring response in the rat brain. First, the elevated protein levels of TGF beta 1 are localized to specific populations of injury-responsive cells in the traumatized CNS. Furthermore, the injection of TGF beta 1 into the brains of injured rats causes a dramatic increase in the scarring response. Conversely, when neutralizing TGF beta 1 antibodies are administered, the deposition of fibrous scar tissue and the formation of a limiting glial membrane that borders the lesion is significantly attenuated, thus establishing a role for the endogenous growth factor in regulation of the non-glial component of the scar. In implicating TGF beta 1 in the scarring response in the CNS, the potential use for TGF beta 1 antagonists as inhibitors of scar formation in the injured mammalian CNS is self-evident.
305 citations
Journal Article•
TL;DR: For suppression of carcinogenesis in vivo, 9cRA was much more potent than all-trans-retinoic acid, both as a single agent or in combination with TAM, although both retinoids had equivalent inhibitory effects on DNA synthesis in cultured human breast cancer cell lines.
Abstract: We show that 9-cis-retinoic acid (9cRA) is a potent inhibitor of mammary carcinogenesis induced by N-nitroso-N-methylurea in Sprague-Dawley rats. Rats were first treated with a single dose of N-nitroso-N-methylurea (50 mg/kg body weight) and then fed non-toxic levels of 9cRA (120 or 60 mg/kg of diet). 9cRA was highly effective in reducing tumor incidence, average number of tumors per rat, and average tumor burden, as well as extending tumor latency. The combination of 9cRA with low levels of tamoxifen (TAM; fed at either 1.0 or 0.5 mg/kg of diet) was particularly effective; addition of 9cRA to a TAM regimen doubled the number of animals that were tumor-free at autopsy and significantly diminished tumor number and tumor burden. For suppression of carcinogenesis in vivo, 9cRA was much more potent than all-trans-retinoic acid, both as a single agent or in combination with TAM, although both retinoids had equivalent inhibitory effects on DNA synthesis in cultured human breast cancer cell lines. Both 9cRA and all-trans-retinoic acid induce the expression of the adhesion molecule, E-cadherin, in the SK-BR-3 cell line. We suggest that clinical evaluation of the combination of 9cRA and TAM, either for chemoprevention or for adjuvant therapy, should be considered.
205 citations
TL;DR: It is demonstrated that the WT1 protein represses expression of the TGF-beta 1 gene through a CGCCCCCGC response element spanning nucleotides -111 to -119 of theTGF- beta 1 promoter, and that theWT1/Egr-1 consensus element of the human TGF -beta 1 promoter plays a critical role in this repression.
Abstract: The Wilms' tumor suppressor gene (WT1) encodes a zinc finger DNA binding protein which functions as a transcriptional repressor. In this study we investigated whether the human transforming growth factor-beta 1 (TGF-beta 1) gene might be a target for transcriptional repression mediated by WT1. Using constructs of the TGF-beta 1 promoter linked to the chloramphenicol acetyl transferase gene, we have demonstrated that the WT1 protein represses expression of the TGF-beta 1 gene through a CGCCCCCGC response element spanning nucleotides -111 to -119 of the TGF-beta 1 promoter. We have also shown in a cotransfection assay that Egr-1, an immediate early growth response gene, activates transcription of the TGF-beta 1 gene through the same response element and that WT1 represses both the basal and Egr-1-induced TGF-beta 1 promoter activity in monkey kidney CV-1 cells. Moreover, WT1 and Egr-1 proteins interact directly with the WT1/Egr-1 response element of the TGF-beta 1 promoter in gel mobility shift assays. These findings provide further definition of transcriptional control of the TGF-beta 1 gene by showing that the WT1 gene product suppresses TGF-beta 1 transcription and that the WT1/Egr-1 consensus element of the human TGF-beta 1 promoter plays a critical role in this repression.
203 citations
Journal Article•
TL;DR: In vitro, Ro24-5531 was 10-100 times more potent than 1,25-dihydroxyvitamin D3 for inhibition of proliferation of human breast cancer cell lines as well as primary cultures of cells from 2 patients with acute myelogenous leukemia.
Abstract: We have used the vitamin D analogue, 1α,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol (Ro24-5531), for inhibition of mammary carcinogenesis induced by N -nitroso- N -methylurea (NMU) in Sprague-Dawley rats. Rats were first treated with a single dose of either 15 or 50 mg/kg body weight NMU and then fed Ro24-5531 (2.5 or 1.25 nmol/kg of diet) for 5–7 months. Ro24-5531 significantly extended tumor latency and lessened tumor incidence as well as tumor number in rats treated with the lower dose of NMU. In rats treated with the higher dose of NMU, Ro24-5531 was fed in combination with tamoxifen; in these experiments, Ro24-5531 significantly enhanced the ability of tamoxifen to reduce total tumor burden, as well as to increase the probability that an animal would be tumor free at the end of the experiment. In vitro , Ro24-5531 was 10–100 times more potent than 1,25-dihydroxyvitamin D3 for inhibition of proliferation of human breast cancer cell lines as well as primary cultures of cells from 2 patients with acute myelogenous leukemia. When fed chronically, Ro24-5531 did not elevate serum calcium in the present studies. We propose the new term, “deltanoids,” for the set of molecules composed of vitamin D and its synthetic analogues, in a manner similar to the naming of “retinoids” for the corresponding set of molecules related to vitamin A.
152 citations
Journal Article•
TL;DR: The data suggest that the NRP-152 and N RP-154 cell lines are suitable systems for analysis of normal prostate growth and prostatic carcinogenesis.
Abstract: We have established two new epithelial cell lines (NRP-152, NRP-154), with markedly different properties, from the dorsal-lateral prostate of Lobund/Wistar rats treated with N -methyl- N -nitrosourea and testosterone propionate. NRP-152 cells do not form tumors in athymic mice and retain many of the properties of normal prostatic epithelial cells. They produce prostatic acid phosphatase, have functional androgen receptors, and require the combination of several growth factors in addition to serum for optimal growth. Their growth is stimulated by epidermal growth factor, insulin, dexamethasone, cholera toxin, dihydrotestosterone, and testosterone, and their growth is inhibited by transforming growth factor βs and retinoic acid. These cells also respond to 1,25-dihydroxy-vitamin D 3 with an early growth stimulation followed by growth inhibition at later times. In contrast, tumorigenic NRP-154 cells lack detectable androgen receptor mRNA and have less stringent growth factor requirements for optimal growth. Growth of NRP-154 cells is stimulated by dexamethasone and insulin, inhibited by transforming growth factor β1, but not significantly altered by epidermal growth factor, cholera toxin, dihydrotestosterone, retinoic acid, or 1α,25-dihydroxyvitamin D 3 . Our data suggest that the NRP-152 and NRP-154 cell lines are suitable systems for analysis of normal prostate growth and prostatic carcinogenesis.
114 citations
TL;DR: Results indicate that activation of TGF-beta 1 expression is one of the cellular responses of PC12 cells to NGF and suggest that T GF-beta may play a role in the differentiation of sympathetic neurons.
95 citations
TL;DR: Results suggest that TGF-β 2 and β 3 may play important roles and act through both autocrine and paracrine mechanisms in the development of many tissues in the chicken.
72 citations
Journal Article•
TL;DR: All three TGF-beta mRNAs were detected in the maxillary territory in vivo before the arrival of the earliest axons and their levels rose throughout the period in which sensory axons reach this territory.
Abstract: We have investigated if transforming growth factor-beta (TGF-beta) isoforms influence the level of expression of nerve growth factor (NGF) mRNA and neurotrophin-3 (NT-3) mRNA in embryonic tissues innervated by neurons that depend on NGF and NT-3 for survival. Presumptive dermal and epidermal cells from the maxillary territory of the embryonic mouse trigeminal ganglion were cultured in defined medium during the early stages of innervation when trigeminal neurons switch their survival dependence from NT-3 to NGF. In E11 and E12 cultures, when the in vivo levels of NGF mRNA and NT-3 mRNA are increasing, TGF-beta 1, TGF-beta 2 and TGF-beta 3 each increased the level of NGF mRNA but had no effect on NT-3 mRNA. In E13 cultures, when the in vivo levels of NGF mRNA and NT-3 mRNA reach a peak (relative to actin mRNA) prior to a marked fall in the level of NT-3 mRNA and a gradual decrease in the level of NGF mRNA, TGF-beta s promoted further increases in the level of NGF mRNA but caused a decrease in the level of NT-3 mRNA. All three TGF-beta mRNAs were detected in the maxillary territory in vivo before the arrival of the earliest axons and their levels rose throughout the period in which sensory axons reach this territory.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: It is shown that inhibition of expression of the cartilage phenotype by retinoic acid in epiphyseal chondrocytes is associated with positive regulation of AP‐1 responsive metalloprotease genes, as well as induction of gene expression for the two components of the transcription factor AP‐ 1, c‐fos and c‐jun.
Abstract: Retinoic acid has been identified as a key morphogen governing pattern formation in the developing cartilaginous skeleton. Retinoids have also been implicated in the premature closure of the cartilage growth plate following vitamin A intoxication or administration of retinoids for dermatologic conditions. Previous studies of the mechanism of action of retinoids in non-chondrogenic cells have concluded that retinoic acid is a negative regulator of AP-1 responsive metalloprotease genes. We show that inhibition of expression of the cartilage phenotype by retinoic acid in epiphyseal chondrocytes is associated with positive regulation of AP-1 responsive metalloprotease genes, as well as induction of gene expression for the two components of the transcription factor AP-1, c-fos and c-jun. Despite the similar effects of TGF-β1 on expression of cartilage matrix proteins and metalloproteases in this culture system, no appreciable changes in the expression of TGF-β isoforms were evident in response to retinoic acid treatment. The present investigation demonstrates that regulation of AP-1 responsive genes by retinoic acid can be either positive or negative, depending on the target cell type, and illuminates new mechanisms by which retinoic acid and other retinoids may exert control during development and growth of the limb. © 1994 wiley-Liss, Inc. 1
TL;DR: A TGF-beta 1 mutant with Cys77 replaced by serine has been expressed in stably transfected Chinese hamster ovary cells and purified to homogeneity, and shows preferential cross-linking to type I rather than type II receptors.
Journal Article•
TL;DR: A grading system for the evaluation of the histogenesis of neoplastic lesions of the prostate and seminal vesicle of the laboratory rat and the measurement of the effects of the synthetic retinoid, 4-hydroxyphenyl retinamide, on prostatic carcinogenesis in the Lobund-Wistar rat is described.
Abstract: We have developed a grading system for the evaluation of the histogenesis of neoplastic lesions of the prostate and seminal vesicle of the laboratory rat. Prostatic and seminal vesicle carcinomas were induced in Lobund-Wistar rats by initiation with 30 mg/kg N-nitroso-N-methylurea i.v., followed by promotion with 40 mg testosterone propionate implants 1 week later and at 3-month intervals thereafter. Experimental and control groups were sacrificed at various time points between 5 and 11 months after dosing with N-nitroso-N-methylurea in order to visualize progressive stages of carcinogenesis of the dorsolateral prostate, the anterior prostate, and the seminal vesicle. A system of staging was created which allows three different categories (in situ change, invasion, desmoplasia) of tumor development to be ranked progressively in a manner conducive to nonparametric analysis. Each category was then further subdivided to create a total of six stages. This system can be used to evaluate agents which modify tumor induction or suppression. The application of this staging system to the measurement of the effects of the synthetic retinoid, 4-hydroxyphenyl retinamide, on prostatic carcinogenesis in the Lobund-Wistar rat is described.
TL;DR: The results of a study in which five patients with hormonally unresponsive prostatic carcinoma and seven patients responding to a luteinising hormone-releasing hormone analogue had prostate biopsies taken before and during treatment illustrate that the epithelial growth inhibitor TGF-beta 1 can be induced by hormonal manipulation in prostate cancer in vivo, and may continue to be up-regulated even after relapse.
Abstract: Transforming growth factor beta-1 (TGF-beta 1) has been proposed as a mediator of tumour growth in a number of tumours and cell lines including prostate, and in a recent study was shown to be up-regulated in the stroma of breast cancer tissue following treatment with the anti-oestrogen tamoxifen. Immunolocalisation of the intracellular form of TGF-beta 1 confirmed that the source of the stromal TGF-beta 1 was the peritumoral fibroblasts. We present here the results of a study in which five patients with hormonally unresponsive prostatic carcinoma and seven patients responding to a luteinising hormone-releasing hormone analogue had prostate biopsies taken before and during treatment. These were stained for TGF-beta expression prior to treatment and at either relapse or 3 months later respectively. Six of seven clinically responding tumours and three of five relapsed tumours showed up-regulation of extracellular TGF-beta 1, again primarily in the stroma, with no apparent up-regulation of intracellular TGF-beta 1, TGF-beta 2 or TGF-beta 3. These data illustrate that the epithelial growth inhibitor TGF-beta 1 can be induced by hormonal manipulation in prostate cancer in vivo, and may continue to be up-regulated even after relapse. This suggests that relapse of hormonally treated prostate cancer may be associated with a failure of the epithelium to respond to stromal TGF-beta 1.
TL;DR: It is demonstrated that a recently cloned human leukemic cell line (FLG 29.1 cells) synthesize and secrete TGF‐β1 and that exogenous or autocrine TGF•β1 can induce the same features of osteoclastic‐like cells, exerting its effects through the binding to T GF‐β specific receptors.
Abstract: Increasing evidence suggests that transforming growth factor-beta (TGF-beta) is involved in bone formation during remodeling. Using a recently cloned human leukemic cell line (FLG 29.1 cells) we demonstrate that these cells synthesize and secrete TGF-beta 1 and that exogenous or autocrine TGF-beta 1 can induce the same features of osteoclastic-like cells, exerting its effects through the binding to TGF-beta specific receptors. Scatchard analysis of 125I-labeled TGF-beta 1 to FLG 29.1 cells revealed the presence of a single high affinity binding site with a Kd value of approximately 25 pM and a binding capacity of approximately 900 sites/cell. Affinity labeling experiments showed that FLG 29.1 cells express type I and type II TGF-beta receptors. Stimulation of FLG 29.1 cells with low TGF-beta 1 doses reduced cell proliferation and increased cell adhesion and tartrate resistant acid phosphatase (TRAcP) activity. Pretreatment of FLG 29.1 cells with TGF-beta 1 caused a significant and dose-dependent response to calcitonin. Northern blot of total mRNA and analysis of the conditioned media (CM) showed that TGF-beta 1 was synthesized by FLG 29.1 cells. TPA treatment, which induces partial differentiation of these cells, markedly increased TGF-beta 1 mRNA expression and growth factor release. The majority of TGF-beta 1 secreted by TPA-treated cells was in its latent form. However, anti-TGF-beta antibodies inhibited TGF-beta 1 and TPA-induced growth inhibition, calcitonin responsiveness, and TRAcP activity, suggesting that the TPA effect is mediated in part by autocrine TGF-beta 1 and indicating that the cells can activate and respond to the TGF-beta that they secrete. These findings support a potential autocrine role for TGF-beta 1 in osteoclast differentiation.
TL;DR: Two mutant TGF-beta s are designed and synthesized on the basis of the crystal structure of T GF-beta 2 and they inhibited the growth of Mv1Lu mink lung epithelial cells and LS1034 colorectal cancer cells but were much less potent at inhibiting the Growth-inhibited cells.
Abstract: Transforming growth factor-beta (TGF-beta) is a potent regulator of cell growth and differentiation. On the basis of the crystal structure of TGF-beta 2, we have designed and synthesized two mutant TGF-beta s, TGF-beta 1 (71 Trp) and TGF-beta 1 (delta 69-73). Although both of these molecules inhibited the growth of Mv1Lu mink lung epithelial cells and LS1034 colorectal cancer cells, which are affected equally by TGF-beta 1 and TGF-beta 2, TGF-beta 1 (delta 69-73) was much less potent than TGF-beta 1 or TGF-beta 1 (71 Trp) at inhibiting the growth of LS513 colorectal cancer cells which are growth-inhibited by TGF-beta 1 but not TGF-beta 2. Both TGF-beta 1 (71 Trp) and TGF-beta 1 (delta 69-73) increased levels of mRNAs for fibronectin and plasminogen activator inhibitor with Mv1Lu cells, whereas only TGF-beta 1 (71 Trp) and not TGF-beta 1 (delta 69-73) up-regulated the mRNA level of carcinoembryonic antigen in LS513 cells. The expression level of carcinoembryonic antigen mRNA in LS1034 cells was not altered by either wild-type or mutant TGF-beta s. Receptor labeling experiments demonstrated that TGF-beta 1 (71 Trp) bound with high affinity to the cell-surface receptors of Mv1Lu, LS1034, and LS513 cells while TGF-beta 1 (delta 69-73) bound effectively to the receptors of Mv1Lu and LS1034 cells but much less to the receptors on LS513 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Journal Article•
TL;DR: The results suggest that one of the mechanisms for acquisition of 1,25-Dihydroxyvitamin D3 resistance induced by E1A may involve loss of vitamin D receptor inducibility by 1, 25-(OH)2D3.
Abstract: 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] inhibited DNA synthesis in transformed mouse keratinocytes (Pam212) in a time- and dose-dependent manner as measured by [3H]thymidine incorporation. To investigate the mechanism through which 1,25-(OH)2D3 acts, we examined its effects on Pam212 cells further transformed with the E1A oncogene. Here, we show that transformation of the cells with the E1A oncogene induced resistance to the effects of 1,25-(OH)2D3 on inhibition of growth of Pam212 cells. While 1,25-(OH)2D3 treatment increased the level of expression of vitamin D receptor mRNA 20-fold in parental cells, the E1A-transformed cells failed to express vitamin D receptor mRNA even after treatment with 1,25-(OH)2D3. Transfection of the E1A-transformed cell line with an expression construct encoding the vitamin D receptor restored receptor expression as well as the inhibition of growth by 1,25-(OH)2D3. These results suggest that one of the mechanisms for acquisition of 1,25-(OH)2D3 resistance induced by E1A may involve loss of vitamin D receptor inducibility by 1,25-(OH)2D3.