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Independent Regulation of Growth and SMAD-mediated Transcription by Transforming Growth Factor ß in Human Melanoma Cells¹

Department of Dermatology and Cutaneous Biology, Jefferson Medical College [U. R., T. K., A. M.], Jefferson Institute of Molecular Medicine [U. R., A. M.], and the Kimmel Cancer Center [U. R.], Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Increased production of transforming growth factor ß (TGF-ß) coupled with resistance to the growth-inhibitory effects of TGF-ß is characteristic of several types of neoplasia including human melanoma. In select epithelial malignancies, lack of TGF-ß-induced growth inhibition is associated with disruptions of TGF-ß-dependent SMAD signaling and transcription. In contrast, the results of the present study indicate intact SMAD-dependent transcription in human melanoma cells, regardless of their proliferative response to exogenous TGF-ß. Furthermore, in some melanoma cell lines constitutive SMAD-dependent transcription was observed, which was due in part to endogenous TGF-ß. These results establish that resistance of melanoma cells to TGF-ß-induced growth inhibition occurs independently of intact TGF-ß receptor/SMAD-mediated transcriptional regulation. They also suggest that melanoma-derived TGF-ß may exert autocrine effects on SMAD-sensitive target genes.

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