Inhibitor Pump

There has been much specu lation regarding which ofthe known ang iogen ic substanc esproduced by macrophages might be key positive regulators of wound neovascularization.Through reversetranscrip tase PCR analysis, mRNA from a variety of po tential angiogenic factors has been identified. Clearly, the induction and regulation of ang iogenes is by macrophages may involve redundancy, so that any single factor may not be essential for ad equ a te wound repair.To add to the complexity, wound macrophages are capable of modu latingother pa rame te rs of wound repair, such as the clearance of debris andtissue regrowth, and it is likely that some macrophagederived factors may affect more than one aspect of wound repair.Although specific macrophage functions may not be sepa rab le in vivo, the regeneration of the cellular and connectivetissue componen ts cannot proceed without the recruitment of new vasculature for nu tr ient suppor t.One of the most convincing pieces of evidence linking a wellknown macrophagederived product, the multifunction matrix glycoprotein th rombospond in, to the inhibition of angiogenesis emerged from investigat ions in tothe function of tumor suppressor genes. It is wellknown that the processes of malignant transformation and tumor progression are characterized by the activation of oncogenes and the loss or inactivation of multiple tumor suppressor genes. While the identity and mechanism of action of many oncogenes are known, by comparison very few tumor suppressor genes have been identified, and less is known about their function at the physiological level.Using the techn ique of Oseltamivir phosphate somatic cell hybridization, these investigators showed tha t, when normal nonangiogenic fibroblasts were fused to the potently angiogenic transformed BHK baby hamster kidney fibroblast line that had lost a single tumor suppressor gene, the resu ltant hybrids behaved like the nontransformed fusion partner.One of the transformed pheno types that was corrected in the se hybrids was that they were now unab le to induce angiogenesis.They showed that nontransformed BHK cells that con ta ined an active tumor suppressor gene secreted an inhibitor of neovascularization, whereas cells which had lost th is suppressor gene did not.A de tailedbiochem ica l, immuno log ic, and functional analysis of th is angiogenic inhibitory activity revealed it to be a trunca ted form of TSP.The significance of th is observation will be discussed more fully in the context of tumor neovascularization.TSP is one member of a family of five homo logouspro te ins.Its modu larstruc ture in part enab les it to interact with a variety of extracellular matrixpro te ins, cell surface and serum pro te in, and cations.TSP ispre sent in great abundance in thepla te let a lpha granu les and is secre ted by a wide variety of epithelial and mesenchymal cells. It has been shown to partic ipa te in cell subst ra te in teractions where many cells have been shown to attach, spread, and migrate on inso lub le TSP. As discussed above, TSP was first implicated as an inhibitor of Denatonium benzoate neovascularization when an antiang iogen ic hams ter pro te in whose secretion was controlled by a tumor supp ressor gene was found to have an am ino acid sequence similar to th at of humanpla te let TSP.

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