Tissue inhibitor of
metalloproteinase-3
(TIMP3, TIMP-3)

Sorsby fundus dystrophy, pseudoinflammatory(SFD)

Gene: the TATA-less TIMP-3 gene maps to 22q12.1-q13.2 (Apte S.S. et al., 1994). It contains 5 exons and 4 introns and extends over approximately 55 kb of genomic DNA. While the first 112 bases of the promoter , which harbour multiple Sp1 sites, were found to suffice for high basal level activity, the adjacent region spanning positions -463 and -112 was found to be a major determinant of serum inducibility (Wick M. et al., 1995).
mRNA: three distinct TIMP-3 mRNAs, with sizes of 5.0, 2.6, and 2.4 kb, were found by Wilde C.G. et al. (1994), presumably due to the usage of alternative polyadenylation signals. TIMP-3 mRNAs were expressed in many tissues, with highest expression in the placenta. The 5.0-kb transcript was predominant in all tissues except the placenta. Uría J.A. et al. (1994) reported hybridization of TIMP-3 cDNA to five mRNA species of 5, 2.7, 2.4 (predominant in placenta), 1.6, and 1.1 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. The TIMP-3 cDNA predicts a 188 amino acids (aa), 21.6 kDa mature TIMP-3. The protein is quite basic (isoelectric point: 9.04) and includes a N-linked glycosylation site near the carboxyl terminus. Both the nucleotide sequence and the deduced translation product of the TIMP3 cDNA has a high degree of similarity to the TIMP-1 (40.1%) and TIMP-2 (44.9%), including 12 conserved cysteinyl residues at the same relative positions (Uría J.A. et al., 1994).
Unlike other TIMP family members, TIMP-3 binds to the extracellular matrix.
See also: TIMPs.

Cell lines:

Tumors:
- Hybridization of TIMP-3 cDNA to five mmRNA species of 5, 2.7, 2.4, 1.6, and 1.1 kb was observed in 3/3 primary breast tumors. The origin of these transcripts (carcinoma or stromal cells) was not investigated (Uría J.A. et al., 1994).

- In situ RNA hybridizations demoonstrated that in breast carcinoma the TIMP3 gene was predominantly expressed by fibroblastic cells within the tumor stroma adjacent to cancer cells (Byrne J.A. et al., 1995).

- Breast carcinoma were transfected withh TIMP-3 expression plasmids and injected subcutaneously into nude mice. Growth curves of the resulting tumors over a period of 6 to 8 weeks demonstrated that increased expression of TIMP-3 resulted in a statistically significant suppression of tumor growth. Deposition of TIMP-3 in the surrounding extracellular matrix by tumor cells may inhibit tumor growth by preventing local expansion of tumor, retarding the release of growth factors sequestered in extracellular matrix, or inhibiting angiogenesis. TIMP-3 over-expression had no effect on the growth of the two tumor cell lines in vitro (Anand-Apte B. et al., 1996).

- Epigenetic inactivation (by methylatioon) of TIMP-3 promoter appeared to be frequent in human cancers, including breast cancer, while normal corresponding tissue showed no evidence for methylation of the CpG island (Bachman K.E. et al., 1998).

Anand-Apte B. et al. (1996) A review of tissue inhibitor of metalloproteinases-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth. Biochem. Cell. Biol. 74, 853-862. (PubMed)
Apte S.S. et al. (1994) Cloning of the cDNA encoding human tissue inhibitor of metalloproteinases-3 (TIMP-3) and mapping of the TIMP3 gene to chromosome 22. Genomics 19, 86-90. (PubMed)
Bachman K.E. et al. (1999) Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggests a suppressor role in kidney, brain, and other human cancers. Cancer Res. 59, 798-802. (PubMed)
Byrne J.A. et al. (1995) The tissue inhibitor of metalloproteinases-3 gene in breast carcinoma: identification of multiple polyadenylation sites and a stromal pattern of expression. Mol. Med. 1, 418-427. (PubMed)
Stohr H. et al. (1995) Genomic organization of the human tissue inhibitor of metalloproteinases-3 (TIMP3). Genome Res. 5, 483-487. (PubMed)
Uría J.A. et al. (1994) Structure and expression in breast tumors of human TIMP-3, a new member of the metalloproteinase inhibitor family. Cancer Res. 54, 2091-2094. (PubMed)
Wick M. et al. (1995)Structure of the human TIMP-3 gene and its cell cycle-regulated promoter. Biochem. J. 311, 549-554. (PubMed)
Wilde C.G. et al. (1994) Cloning and characterization of human tissue inhibitor of metalloproteinases-3. DNA Cell Biol. 13, 711-718. (PubMed)

Genome Database data (GDB Access Number: 138175)
GeneCard data (TIMP3)
UniGene data (Hs.245188)
OMIM data (ID = 188826)
LocusLink data (LocusID = 7078)
Swiss-Prot (ID = P35625)


MMP1, MMP2, MMP3, MMP7, MMP9, MMP11, MMP13, MMP14, MMP15, MMP16, MMP17, TIMP-1, TIMP-2, TIMP-4