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Structure and Expression in Breast Tumors of Human TIMP-3, a New Member of the Metalloproteinase Inhibitor Family¹

Departamento de Biología Funcional, Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain

A new member of the metalloproteinase inhibitor family of proteins has been cloned from a complementary DNA library derived from a human breast tumor. The isolated complementary DNA contains an open reading frame 633 base pairs long, encoding a polypeptide of 211 amino acids, which has been called tissue inhibitor of metalloproteinase 3 (TIMP-3). This protein displays low sequence similarity to the previously known human TIMPs but shows a high degree of similarity with chicken inhibitor of metalloproteinase 3, a recently described metalloproteinase inhibitor stimulated during oncogenic transformation of chicken fibroblasts and with the ability to promote some phenotypic properties of transformed cells. Northern blot analysis of RNA from human tissues revealed that the TIMP-3 gene is expressed in placenta and uterus but not in liver and ovary. In addition, TIMP-3 transcripts were detected in all breast carcinomas examined. On the basis of these expression data in breast tumors, together with its high degree of structural homology with chicken inhibitor of metalloproteinase 3, a possible role for human TIMP-3 in the regulation of connective tissue turnover and remodeling is proposed.

¹ This work was supported by grants from Comisión Interministerial de Ciencia y Tecnología (SAL91-0617) and Plan FEDER-European Community. J. A. U and J. P. F are recipients of a fellowship from FICYT-Asturias (Spain). The nucleotide sequence reported in this paper has been submitted to the GenBank^TM/EMBL Data Bank with Accession No. X76227.

² To whom requests for reprints should be addressed.

Received 1/12/94. Accepted 3/ 4/94.

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