Tissue inhibitor of
metalloproteinase-4
(TIMP4, TIMP-4)

Other name(s)

???

Molecular biology

Gene: maps to 3p25. Like other members of the TIMP family, the TIMP-4 protein is encoded by 5 exons. These span 6 kb of genomic DNA, so that TIMP-4 is similar in size to TIMP-1, but considerably smaller than TIMP-2 and TIMP-3. The exon-intron boundaries of TIMP-4 are at locations very similar to those of the other TIMP genes, demonstrating the high degree of conservation of gene structure in this family (Olson T.M. et al., 1998).
mRNA: size: 1.4-kb
Protein: the tissue inhibitors of metalloproteinases (TIMPs) are natural inhibitors of the matrix metalloproteinases, a group of zinc-binding endopeptidases involved in the degradation of the extracellular matrix. TIMP-4 is a 224-amino acid polypeptide 37% similar to TIMP-1 and 51% similar to TIMP-2 and TIMP-3. Expressed TIMP-4 inhibits matrix metalloproteinases (MMPs) in vitro (Greene J. et al., 1996).
See also: TIMPs.

Breast cancer

Cell lines:
- recombinant TIMP-4 (rTIMP4p), expresseed in baculovirus-infected insect cells, was purified to homogeneity. It demonstrated a strong inhibitory effect on the invasion of human breast cancer cells across reconstituted basement membranes (Liu Y.E. et al., 1997).

Tumors:
- A full-length TIMP-4 cDNA was transfeccted into MDA-MB-235 breast cancer cells (BCC). TIMP-4-435 clones expressed TIMP-4 mRNA and produced anti-metalloproteinase (MMP) activity, while control clones did not express TIMP-4 mRNA or produce detectable anti-MMP activity. Overexpression of TIMP-4 inhibited the invasion potential of the cells in the in vitro invasion assay. When injected orthotopically into nude mice, TIMP-4 transfectants were significantly inhibited in tumor growth by 4-10-fold in primary tumor volumes; and in axillary lymph node and lung metastasis as compared with controls (Wang M. et al., 1997).

References

Greene J. et al. (1996) Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. J. Biol. Chem. 271, 30375-30380. (PubMed)
Liu Y.E. et al. (1997) Preparation and characterization of recombinant tissue inhibitor of metalloproteinase 4 (TIMP-4). J. Biol. Chem. 272, 20479-20483. (PubMed)
Olson T.M. et al. (1998) Cloning of the human tissue inhibitor of metalloproteinase-4 gene (TIMP4) and localization of the TIMP4 and timp4 gens to human chromosome 3p25 and mouse chromosome 6, respectively. Genomics 51, 148-151. (PubMed)
Wang M. et al. (1997) Inhibition of tumor growth and metastasis of human breast cancer cells transfected with tissue inhibitor of metalloproteinase 4. Oncogene 14, 2767-2774. (PubMed)