This often results in structurally altered proteins, truncated gene products, or normal proteins that are overexpressed and evade appropriate feedback control mechanisms.To date, in excess of oncogenes have been identified.The important point to remember is that the Cyclosporine products of these growth stimulatory genes, when activated or overexpressed, Mebeverine hydrochloride function in a dominant fashion, since an alteration in only one of the two copies of the gene is necessary for it to exert its effect.Tumor suppressor genes, on the other hand, function in an entirely different manner.As a group, these genes negatively regulate cell growth.The protein products encoded by these genes, of which about a dozen or so have been cloned, include cellcycle regulatory proteins, and signal transduction proteins. The proteins encoded by several other cloned tumor suppressors as well as other candidate genes remain unclear at this time.Of particular interest, however, are recent studies which suggest that an important target for some tumor suppressors are genes whose products regulate angiogenesis.They showed that an immortal but nontumorigenic line of hamster fibroblasts, BHK cl cells, could be converted to malignancy and anchorage independence by loss of a functioning tumor suppressor gene.These cells were highly tumorigenic in nude mice and neonatal hamsters and were potently angiogenic in vivo.The presence of inhibitory activity was found to be tightly linked to the presence of an active suppressor gene in transformants and their revertants, in segregating cell hybrids, and in temperaturesensitive transformants.When endothelial cell chemotaxis was used as an in vitro corollary of angiogenesis in the rat cornea model of neovascularization, the inhibitor was purified and shown to be the wellknown matrix glycoprotein TSP. This work, for the first time, established a new function for a tumor suppressor gene: the regulation of the production of a naturally occurring inhibitor of angiogenesis.These individuals have inherited one wildtype allele and one mutant allele of the p gene.As a result, they have an increased risk of developing sarcomas and other tumors when the second allele is lost.These workers found that when the wildtype allele was lost in these fibroblasts, the cells acquired potent angiogenic activity coincidental with loss of production of the angiogenesis inhibitor TSP.Transfection assay revealed that p was able to stimulate the endogenous TSP gene and positively regulate TSP promoter sequences.Suppressor gene loss also leads to downregulation of an inhibitor of angiogenesis in keratinocytes progressing toward tumorigenicity in vivo.TSP is found in the condit ioned media of normal keratinocytes but ispresent at reduced levels in CM of initiated keratinocytes and in some cases is unde tec ted in tumor CM. This same ph enom enon seems to occur in human tumo rs, for when a tumor supp ressor gene is reintroduced into cultured human neu rob las toma or os teosa rcoma lines, cells begin to make an inhibitor of angiogenesis. There is a lso indirect evidence suggesting a role forother tumor supp resso rs in the control of ang iogenes is.Humanos teo sa rcoma and neu rob las toma tumor cell lines which have reverted to nontumorigenicity following the introduction of either ch romosome, the retinob las toma, or the p suppressor genes become nonangiogenic and begin to produce an inhibitor of ang iogenes is.