Disease relevance of Col4a3

• Col4a3(-/-) mice, a model for autosomal recessive Alport syndrome, progress to renal failure significantly slower on the C57BL/6 than on the 129X1/Sv background [1].
• Insertional mutation of the collagen genes Col4a3 and Col4a4 in a mouse model of Alport syndrome [2].
• We previously reported the therapeutic efficacy of antiangiogenic tumstatin peptide in the early diabetic nephropathy model [3].
• Tumstatin peptide is an angiogenesis inhibitor derived from type IV collagen and inhibits in vivo neovascularization induced by vascular endothelial growth factor (VEGF), one of the mediators of glomerular hypertrophy in diabetic nephropathy [4].
• Glomerular hypertrophy, hyperfiltration, and albuminuria were suppressed by tumstatin peptide (1 mg/kg) in streptozotocin-induced diabetic mice [4].

High impact information on Col4a3

• The tumor-suppressive action of TSP-1, endostatin, and tumstatin correlates with expression of CD36 receptor, alpha5beta1 integrin, and alphavbeta3 integrin on proliferating endothelial cells, respectively [5].
• Increase in renal expression of VEGF, flk-1, and angiopoietin-2, an antagonist of angiopoietin-1, was inhibited by tumstatin treatment in diabetic mice [4].
• Alteration of glomerular nephrin expression, a podocyte protein crucial for maintaining glomerular filtration barrier, was recovered by tumstatin in diabetic mice [4].
• Glomerular matrix expansion, the increase of total glomerular cell number and glomerular endothelial cells (CD31 positive), and monocyte/macrophage accumulation was inhibited by tumstatin peptide [4].
• We previously generated a knockout mouse model of Alport syndrome by mutating Col4a3 [6].

Chemical compound and disease context of Col4a3

• We evaluated the effectiveness of gene therapy, that is, intramuscular delivery of plasmid DNA encoding tumstatin (pSecTag2B-tum), combined with gemcitabine administration in vitro and in vivo, using colon carcinoma (CT26) and Lewis lung carcinoma (LLC) murine models [7].
• Collectively, our results demonstrate that tumstatin or its C-terminal antitumor fragment, Tum 183-232, inhibits in vivo melanoma progression by triggering an intracellular transduction pathway, which involves a cyclic AMP (cAMP)-dependent mechanism [8].

Biological context of Col4a3

• The downregulation or the absence of alpha3/4(IV) collagen chains in the GBM of Lmx1b(-/-) and Col4a3(-/-) mice was found to induce ectopic deposition of alpha5/6(IV) collagen [1].
• Exons 1 through 12 of the collagen IV gene Col4a4, exons 1 and 2 of the adjacent Col4a3 gene, and the intergenic promoter region are deleted [2].
• Tumstatin domain overexpression inhibited B16F1 in vitro cell proliferation, anchorage-independent growth, and invasive properties [8].
• This study suggests that combined treatment by the intramuscular delivery of plasmid DNA encoding tumstatin and gemcitabine augments tumor growth inhibition by suppressing angiogenesis and enhancing apoptosis in murine models [7].
• The NC1 domain of alpha3 chain of type IV collagen, namely tumstatin, has been shown to display specific anti-angiogenic properties by inhibiting endothelial cells' proliferation and inducing their apoptosis via an interaction with alphavbeta3 integrin [9].

Anatomical context of Col4a3

• The suppressive effects of tumstatin require alphaVbeta3 integrin expressed on pathological, but not on physiological, angiogenic blood vessels [10].
• The renatured recombinant tumstatin could specifically inhibit endothelial cell proliferation in a dose-dependent manner, and suppress bFGF-induced angiogenesis in chick embryo chorioallantoic membrane and tumor growth in mouse B16 melanoma xenograft models [11].

Associations of Col4a3 with chemical compounds

• Enhanced antitumor effect of the combination of tumstatin gene therapy and gemcitabine in murine models [7].

Other interactions of Col4a3

• In (129 x B6)F1 Col4a3(-/-) mice, the amount of alpha5/6(IV) collagen in the GBM was inherited in a mother-to-son manner, suggesting that it is controlled by one or more X-linked loci, possibly Col4a6 itself [1].
• Gelatinase B-deficient mice were bred with Col4a3-/- mice, a model for Alport syndrome, to determine whether gelB influences the progression of glomerulonephritis [12].
• Recently, we reported that tumstatin (the NC1 domain of alpha 3 chain of type IV collagen) and its deletion mutant tum-5 possess anti-angiogenic activity [13].
• NGR Enhanced the Anti-Angiogenic Activity of tum-5 [14].

Analytical, diagnostic and therapeutic context of Col4a3

• Until now, the tumstatin anti-angiogenic effect has only been shown by in vitro studies or mouse xenograft experiments [9].

References