Serine-threonine protein kinases, inhibition

Cyclin-dependent kinases (CDKs) are serine-threonine protein kinases that regulate cell cycle progression. These kinases are activated by various cyclins, inhibited by natural inhibitors such as p21, p27, and pl8, and are tightly controlled by transcriptional and posttranscriptional modifications (Sherr and Roberts 1999). Bae et al. (2003) reported that troglitazone-induced cell cycle arrest by this pathway, and apoptosis of hepatoma cell lines ware caused G1 cell cycle arrest through the induction of p53 related proteins and the reduction of cyclin Dl, phospho-RB and CDK activities. 

In turn, MAPKs are also involved in the regulation of the gene expression of all three NOS isoenzymes. The expression of iNOS (NOS-2) is regulated by all three MAP kinase pathways in a variety of cell types [125-129]. For example, INK and ERKl/2 pathways are necessary for lipopolysaccharide (LPS-) and interferon-y-stimulated iNOS expression in mouse macrophage cells, possibly via a-tumor necrosis factor secretion, whereas p38 inhibited induction [130]. The induction of endothelial NOS (eNOS, NOS-3) by estrogen, fibroblast growth factor, or epidermal growth factor in endothelial cells involves the Ras-ERK pathway [131,132]. eNOS is phosphorylated, and thus activated, by the serine/threonine protein kinase Akt, which is recruited to the cell membrane by PI3-kinase as an antiapoptotic mechanism in the response of endothelial cells to shear stress [133]. 

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