Disease relevance of TIMP3

• Transfection of cytomegalovirus (CMV) promoter-Sp1 plasmid increased TIMP-3 promoter (-940 to +376)-driven luciferase activity [1].
• Unlike many of the recently described genes that cause human retinal disease, TIMP-3 is preferentially expressed in the RPE of the normal eye, as opposed to the photoreceptors [2].
• Expression of TIMP-3 in the RPE is consistent with the recent demonstration of TIMP-3 mutations in patients with Sorsby's fundus dystrophy, a condition marked by the early onset of choroidal neovascularization in the macula [2].

High impact information on TIMP3

• We examined responsiveness of the TIMP-3 gene to OSM in articular chondrocytes and studied the regulatory and signaling mechanisms of this response [3].
• OSM induced TIMP-3 mRNA and protein expression in a dose- and time-dependent fashion [3].
• Thus, ROS mediate TGF-beta1-induced TIMP-3 gene expression [4].
• Hydrogen peroxide, a ROS, induced TIMP-3 RNA [4].
• Smad2 phosphorylation was independent, and TIMP-3 expression was dependent, on new protein synthesis [4].

Biological context of TIMP3

• TGF-beta did not alter stability of the TIMP-3 transcripts in RNA decay time-courses, suggesting a transcriptional control [5].
• DNA sequencing of bovine TIMP-3 cDNA revealed an open reading frame of a 211-amino-acid protein containing signal peptide and 12 conserved cysteines [5].
• These results suggest that the expression of MMPs-2, 3 and 9 and TIMP-3 is likely to be discoordinately regulated due to interaction with collagen and/or TGF-beta1 in bovine endometrium, and thereby different sets of MMPs may be associated with ECM remodeling during implantation and placentation in vivo [6].

Anatomical context of TIMP3

• Freshly released chondrocytes constitutively expressed three transcripts of TIMP-3 that are induced by serum factors [5].
• To clarify the mechanism of extracellular matrix (ECM) remodeling in bovine endometrium, we investigated the regulation of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases-3 (TIMP-3) in bovine endometrial stromal cells (BESCs) on type-I collagen gel [6].
• Localization of TIMP-3 mRNA expression to the retinal pigment epithelium [2].
• TIMP-3 mRNA expression was detected strongly in the retinal pigment epithelium (RPE) and to a minor extent in the ciliary epithelium, but not at any other site within the eye [2].
• In bovine synovial fibroblasts, TNF-alpha did not affect a recently identified inhibitor, TIMP-3, but induced stromelysin mRNA expression in a dose- and time-dependent fashion (3- to 5-fold) which required de novo protein synthesis [7].

Associations of TIMP3 with chemical compounds

• Reduced glutathione and L-cysteine also blocked Smad2 and TIMP-3 induction by TGF-beta1, whereas a nonthiol, N-acetylalanine, did not [4].
• An antiinflammatory glucocorticoid, dexamethasone, inhibited the basal, and suppressed partially the TGF-beta-inducible, TIMP-3 expression in primary bovine and human chondrocytes [5].
• RNA decay time-courses suggested that the OSM-mediated increase of TIMP-3 RNA was not due to enhanced message stability and, along with inhibition by actinomycin-D, suggested a transcriptional control [3].
• H7 and genistein also suppressed TGF-beta-induced TIMP-3 protein expression [8].
• H7, a serine/threonine protein kinase inhibitor, markedly reduced the response of TIMP-3 gene to TGF-beta [8].

Other interactions of TIMP3

• We examined the implication of protein kinases in the TGF-beta-mediated induction of TIMP-3 expression by utilizing activators and inhibitors of these enzymes [8].
• TIMP-3 protein was localized to granulosal and thecal layers of preovulatory follicles and adjacent ovarian stroma, whereas TIMP-4 immunoreactivity was localized to granulosal and thecal cells and ovarian blood vessels [9].

Analytical, diagnostic and therapeutic context of TIMP3

• In situ hybridization was performed on frozen sections of albino mouse eyes using riboprobes generated to the 3' untranslated region of TIMP-3 [2].
• Ovaries containing preovulatory follicles were collected at 0, 12 and 20 h after GnRH injection for real-time PCR quantification of TIMP-3 and TIMP-4 mRNAs and immunohistochemical localization studies [9].

References