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Cloning of a Novel Malignant Melanoma-derived Growth-Regulatory Protein, MIA¹

Department of Neurology, University of Würzburg, Josef-Schneider Str. 11, D-97080 Würzburg [A. B., R. A., C. B., B. H., A. S., P. J., U. B.]; Department of Pathology, University of Regensburg, Franz-Josef-Strauss Allee, D-93053 Regensburg [A-K. B., R. B.]; and Max Planck Institute for Biochemistry, Am Klopferspitz, D-82152 Planegg-Martinsried [F. L.], Federal Republic of Germany

Growth and progression of malignant melanoma cells is influenced by a complex network of growth-stimulating and -inhibiting factors produced by both the tumor cells and the local environment. Here we report the purification and molecular cloning of a novel growth regulating protein, designated melanoma inhibitory activity (MIA) and provide a preliminary functional characterization. MIA is translated as a 131-amino acid precursor and processed into a mature 107-amino acid protein after cleavage of a putative secretion signal. A murine complementary DNA was isolated that encoded a MIA-protein with 88% amino acid identity. MIA is secreted into the culture supernatant by several malignant melanoma cell lines as an M_r 11,000 autocrine growth factor and acts as a potent tumor cell growth inhibitor for malignant melanoma cells and some other neuroectodermal tumors, including gliomas. MIA has no homology to any other known protein and, therefore, represents a novel type of growth-regulatory factor. Furthermore, we describe a molecular approach to express functionally active MIA in Escherichia coli, which might be attractive as a future antitumor therapeutical substance.

¹ The work was supported by a grant from the German Cancer Foundation, the Mildred Scheel Stiftung (Ne W75/92 B03; to U.B.) and the Deutsche Forschungsgemeinschaft (to R. B.)

² These authors have made equal contributions.

³ A predoctoral fellow of the DFG (Graduiertenkolleg Therapieforschung Onkologie).

⁴ Present address: Cancer Center, La Jolla Cancer Research Foundation, La Jolla, CA 92037.

⁵ Present address: The Salk Institute for Biological Studies, San Diego, CA 92186-5800.

⁶ To whom requests for reprints should be addressed.

Received 3/ 9/94. Accepted 8/29/94.

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