This finding indicates that in someway, butyrate treatment directly targets these genes and down regulates the genes that are essential for initia tion of DNA replication. inhibitor price CDC2 Cdk1 and related cyclins are also significantly down regulated. At least four roles have now been recognized for cyclin A activated Cdk1 protein kinases in regulating cell cycle events. First, Cdk2 cyclin A is responsible for activating pre replication com plexes at the beginning of S phase in order to begin DNA synthesis. Second, Cdk1 cyclin A inhibits assembly of new pre replication complexes during S phase by inactivating Cdc6. Third, Cdk2 cyclin A is required for the G2 to M phase transition. Finally, Li and DePamphilis recently revealed that Cdk1 cyclin A is required for preventing Orc1 in mammals or ORC in Xenopus from binding to chromatin during mitosis.
Our results show that targeted destruction of cdc6 and cdc2 cdk1 may be involved in the apoptosis and cell cycle arrest induced by butyrate. They are consistent with the growing body of evidence suggesting that disruption of the coordi nation between regulation of DNA synthesis and cyclin dependent kinase activity is an important feature of apop tosis. It is of importance and interest for us to understand the mechanism of how butyrate targets these genes and causes these changes in gene expressions. However, it will require a great deal of efforts and certainly is out of the scope of this report.
Understanding the mechanism of butyrate in affecting apoptosis, cell proliferation and differentiation and espe cially the difference of its mode of action compared to other HDAC inhibitors will facilitate designing novel and more potent HDAC inhibitors that target specific cellular processes that are dysregulated in neoplastic cells. Dissec tion of the pathways regulated by butyrate will provide a basis for better utilization of its anti tumor, anti meta static, immune mediating, and anti inflammatory proper ties. In addition, butyrate has been shown to up regulate transcription levels of muslins, which are the major com ponents of gastrointestinal mucosa considered to be the first line of defense against pathogens. Because of its ability to affect functions of monocyte derived dendritic cells and macrophage and to activate neutrophils, butyrate and its related biological pathways could be manipulated to fight against gastrointestinal pathogens.
Up regulation of glutathione Cilengitide S transferases, genes known to be involved in defense against oxidative stress, by butyrate provides evidence of a favorable modulation of toxicological defense systems. The results presented in this paper not only help to better dissect HDAC inhibition and mechanism in apoptosis and cell cycle control but also help to understand ruminant metabolism and physi ology, which in turn could lead to improvement in energy efficiency of cattle.