Showing papers by "Michael B. Sporn published in 1985"
TL;DR: The cDNA sequence indicates that the 112-amino acid monomeric form of the natural TGF-β homodimer is derived proteolytically from a much longer precursor polypeptide which may be secreted.
Abstract: The partial amino-acid sequence of purified human transforming growth factor-beta (TGF-beta) was used to identify a series of cDNA clones encoding the protein. The cDNA sequence indicates that the 112-amino acid monomeric form of the natural TGF-beta homodimer is derived proteolytically from a much longer precursor polypeptide which may be secreted. TGF-beta messenger RNA is synthesized in various normal and transformed cells.
1,716 citations
TL;DR: The ability of cancer cells to produce and to respond to their own growth factors (autocrine secretion) has become a central concept linking oncogene and growth factor research.
Abstract: The ability of cancer cells to produce and to respond to their own growth factors (autocrine secretion) has become a central concept linking oncogene and growth factor research. Oncogenes confer growth factor autonomy on cells not only by coding directly for autocrine peptide growth factors or their receptors, but also by amplifying the mitogenic signals generated by a growth factor at its receptor. Antagonists of positive autocrine growth factors can inhibit growth of cancer cells in experimental animals. Recently identified negative autocrine growth factors might themselves control aberrant cell growth.
1,404 citations
TL;DR: The data indicate that the effects of TGF-beta on cells are not a function of the peptide itself, but rather of the total set of growth factors and their receptors that is operant in the cell at a given time.
Abstract: Type beta transforming growth factor (TGF-beta) is a two-chain polypeptide of 25,000 daltons isolated from many tissues, including bovine kidney, human placenta, and human platelets. It has been characterized by its ability to stimulate reversible transformation of nonneoplastic murine fibroblasts, as measured by the formation of colonies of these cells in soft agar (ED50 = 4 pM TGF-beta for NRK fibroblasts). We now show that the response of cells to TGF-beta is bifunctional, in that TGF-beta inhibits the anchorage-dependent growth of NRK fibroblasts and of human tumor cells by increasing cell cycle time. Moreover, the anchorage-independent growth of many human melanoma, lung carcinoma, and breast carcinoma cell lines is inhibited by TGF-beta at concentrations in the same range as those that stimulate colony formation of NRK fibroblasts (average ED50 = 10-30 pM TGF-beta for inhibition). Whereas epidermal growth factor and TGF-beta synergize to induce anchorage-independent growth of NRK fibroblasts, their effects on the growth of A-549 human lung carcinoma cells are antagonistic. The bifunctional response of cells to TGF-beta is further demonstrated in Fischer rat 3T3 fibroblasts transfected with a cellular myc gene. In these cells TGF-beta synergizes with platelet-derived growth factor to stimulate colony formation but inhibits the colony formation induced by epidermal growth factor. The data indicate that the effects of TGF-beta on cells are not a function of the peptide itself, but rather of the total set of growth factors and their receptors that is operant in the cell at a given time.
1,080 citations
TL;DR: Cells transformed by Harvey or Moloney sarcoma virus secrete at least 40 times as much type beta transforming growth factor as their respective untransformed control cells, suggesting that transformation causes down-regulation of the type beta transforms growth factor receptor.
Abstract: Cells transformed by Harvey or Moloney sarcoma virus secrete at least 40 times as much type beta transforming growth factor as their respective untransformed control cells. The transformed cells bind only 20 to 50% as much type beta transforming growth factor as the control cells, suggesting that transformation causes down-regulation of the type beta transforming growth factor receptor.
129 citations
TL;DR: It is demonstrated that human TGF-α is as active as murine EGF in promoting eyelid opening in newborn mice and in a dose-dependent eyelidOpening assay that human EGF is as potent as its murine homologue with respect to this biological property.
Abstract: Both murine and human epidermal growth factors (EGFs) are known to cause precocious opening of the eyelids in newborn mice. Another set of peptides that are structurally and functionally homologous to murine and human EGFs are the murine and human type-alpha transforming growth factors (TGF-alpha s), TGF-alpha s have been found in many cancer cells and it has been suggested that their autocrine action may play an important part in malignant transformation. In several in vitro systems murine and human TGF-alpha s are functionally interchangeable with murine and human EGFs. However, the in vivo activity of the TGF-alpha s has not been characterized, as only small amounts of these peptides were available until recently. The cloning of the gene for human TGF-alpha and its expression in Escherichia coli now allow us to demonstrate that human TGF-alpha is as active as murine EGF in promoting eyelid opening in newborn mice. Furthermore, we show in a dose-dependent eyelid opening assay that human EGF is as potent as its murine homologue with respect to this biological property.
91 citations
TL;DR: It is shown that induction of anchorage-independent growth by each of these sets of growth factors involves different cellular pathways which can be distinguished by their sensitivity to retinoic acid.
Abstract: Selective inhibition of the anchorage-independent growth of myc-transfected fibroblasts by retinoic acid
36 citations
TL;DR: The intracellular TGF-beta from the human tumor cell line was similar in all respects tested to normal human placenta and purified to homogeneity as judged by a single peak after reverse-phase high-performance liquid chromatography and a single band on a sodium dodecyl sulfate-polyacrylamide gel.
Abstract: Intracellular transforming growth factors (TGFs) were extracted from a human rhabdomyosarcoma cell line and purified to apparent homogeneity by using gel filtration, cation-exchange, and high-performance liquid chromatography. Two types of transforming growth factor activities, TGF-alpha and TGF-beta, were detected. The intracellular polypeptides which belonged to the TGF-alpha family required TGF-beta for full activity in inducing nonneoplastic normal rat kidney fibroblasts to grow in soft agar. These peptides also bound to the membrane receptor for epidermal growth factor. As determined by sodium dodecyl sulfate-polyacrylamide gels, the apparent molecular weight of these intracellular TGF-alpha's was 18 000. Intracellular TGF-beta required either epidermal growth factor or TGF-alpha for stimulation of soft agar growth. The intracellular TGF-beta was purified to homogeneity as judged by a single peak after reverse-phase high-performance liquid chromatography and a single band on a sodium dodecyl sulfate-polyacrylamide gel. The intracellular TGF-beta from the human tumor cell line was similar in all respects tested (migration on sodium dodecyl sulfate-polyacrylamide gels, stimulation of soft agar growth, binding to the membrane receptor for TGF-beta, and amino acid composition) to intracellular TGF-beta from normal human placenta.
34 citations
Journal Article•
33 citations
TL;DR: Transforming growth factors alpha and beta isolated from normal mouse kidney induced gross morphological changes in rat urothelial cells maintained in organ culture similar to those observed after long-term treatment of rat bladder organ cultures with the carcinogen N-methyl-N-nitrosourea (MNU) or the promoting agents sodium saccharin and sodium cyclamate.
Abstract: Transforming growth factors alpha and beta (TGF-alpha and TGF-beta) isolated from normal mouse kidney induced gross morphological changes in rat urothelial cells maintained in organ culture. These morphological effects are similar to those observed after long-term treatment of rat bladder organ cultures with the carcinogen N-methyl-N-nitrosourea (MNU) or the promoting agents sodium saccharin and sodium cyclamate. Cultures were treated continuously with 5-25 micrograms/ml of Bio-Gel P-30-purified TGF containing both TGF-alpha and TGF-beta between days 1 and 14 in culture, or with 5 micrograms/ml from days 28 to 42. Controls received 1-10 ng/ml epidermal growth factor (EGF) or control medium. Untreated controls retained a normal urothelium throughout the period of study. Mature superficial-type cells covered most of the surface and less mature forms appeared on the cut sides and damaged areas where cells followed the normal pattern of urothelial differentiation. EGF at 5 and 10 ng/ml caused necrosis of the entire urothelium but at 1 and 2 ng/ml had minimal effects on histology and scanning electron microscopical appearance up to 14 days in culture. Crude P-30-purified TGFs induced a series of dose-related changes from 4 days, which were maximal at 8 days and persisted or decreased between 8 and 14 days. These included hyperplasia, loss of epithelial polarity, hyperchromasia and elongation of basal cells between the overlying cell layers to reach the culture surface. Scanning electron microscopy showed the appearance at the culture surface of immature cells with gross surface abnormalities including large numbers of blebs, stubby microvilli and long pleomorphic microvilli. Immature cells on the sides of the culture and in damaged areas developed similar features. At crude TGF doses of 10 micrograms/ml many superficial cells were rounded, some became cystic and epithelial necrosis was observed. Cultures treated with h.p.l.c.-purified TGF-beta at 80 ng/ml in the presence of 2 ng/ml EGF showed similar effects to those treated with 5 micrograms/ml P-30-purified TGF. Fully differentiated cultures treated from 28 to 42 days with crude TGF, showed changes similar to those seen in early cultures. However, histological changes, particularly basal cell elongation were more widespread and there was an abnormal development of globular processes between the membrane ridges of mature superficial cells. Neither crude TGF nor EGF stimulated growth in soft agar of isolated epithelial cells from freshly killed rats or organ cultures pretreated for 7 days with EGF or TGF.(ABSTRACT TRUNCATED AT 400 WORDS)
8 citations