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Department of Histology and Medical Embryology, University of Rome ‘La Sapienza’, 00161, Rome, Italy
1Correspondence: Department of Histology and Medical Embryology, University of Rome ‘La Sapienza’, Via A. Scarpa 14, 00161, Rome, Italy. E-mail: bouche{at}uniroma1.it
Transforming growth factor ß (TGF) is a well-known inhibitor of myogenic differentiation as well as an autocrine product of rhabdomyosarcoma cells. We studied the role of the TGF-ß autocrine loop in regulating growth and myogenic differentiation in the human rhabdomyosarcoma cell line, RD. We previously reported that the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) induces growth arrest and myogenic differentiation in these cells, which constitutively express muscle regulatory factors. We show that TPA inhibits the activation of secreted latent TGF-ß, thus decreasing the concentration of active TGF-ß to which the cells are exposed. This event is mediated by the TPA-induced alteration of the uPA/PAI serine-protease system. Complete removal of TGF-ß, mediated by the ectopic expression of a soluble type II TGF-ß receptor dominant negative cDNA, induces growth arrest, but does not trigger differentiation. In contrast, a reduction in the TGF-ß concentration, to a range of 0.14–0.20 x 10-2 ng/ml (which is similar to that measured in TPA-treated cells), mimics TPA-induced differentiation. Taken together, these data demonstrate that cell growth and suppression of differentiation in rhabdomyosarcoma cells require overproduction of active TGF-ß; furthermore, they show that a ‘critical’ concentration of TGF-ß is necessary for myogenic differentiation to occur, whereas myogenesis is abolished below and above this concentration. By impairing the TGF-ß autocrine loop, TPA stabilizes the factor concentration within the range compatible for differentiation to occur. In contrast, in human primary muscle cells a much higher concentration of exogenous TGF-ß is required for the differentiation inhibitory effect and TPA inhibits differentiation in these cells probably through a TGF-ß independent mechanism. These data thus clarify the mechanism underlying the multiple roles of TGF-ß in the regulation of both the transformed and differentiated phenotype.—Bouché, M., Canipari, R., Melchionna, R., Willems, D., Senni, M. I., Molinaro, M. TGF-ß autocrine loop regulates cell growth and myogenic differentiation in human rhabdomyosarcoma cells.
Key Words: TPA • serine-protease system • muscle regulatory factors • RD cells
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