Cyclin-kinase inhibitors

ScHWOB, E., Bohm, T., Mendenhall, M. D., and Nasmyth, K. The B-type cyclin kinase inhibitor p40SICl controls the Cl to S transition in S. cerevisiae. Cell 1994, 79, 233-44. 

The cyclosome (or APC) is a high molecular weight complex that degrades proteins containing a specific recognition sequence, the destruction box (see chapter 13.2.4). Substrates are cell cycle regulators as e.g. cyclins, kinase inhibitors and spindle-associated proteins. Importantly, some forms of the cyclosome require phosphorylation in order to be active (fig. 2.15B). It is still unclear which of the many subunits carries the E3 enzyme activity. 

B. Cyclin-dependent Kinase-2/Cyclin Kinase Inhibitors... 

In a subsequent investigation by the author (7), cdk2/cyclin kinase inhibitors were prepared consisting of (5-bromo-l,3-thiazol-2-yl)amino derivatives, (VII), and were effective as cytotoxic agents without producing indiscriminate damage to both normal and tumor cells. 

Substrates are cell cycle regulators as, e.g., cyclins, kinase inhibitors and spindle-associated proteins. Importantly, some forms of the cyclosome require phosphorylation in order to be active. 

Lawson BR, Baccala R, Song J, Croft M, Kono DH, Theofilopoulos AN (2004) Deficiency of the cyclin kinase inhibitor p21 (WAF-1/CIP-1) promotes apoptosis of activated/memory T cells and inhibits spontaneous systemic autoimmunity. J Exp Med, 199 547-557. 

The production and constitutive activation of Ras° protein are not sufficient to cause transformation of normal cells In a primary (fresh) culture of human, rat, or mouse fibroblasts. Unlike cells In a primary culture, however, cultured 3T3 cells have undergone a loss-of-functlon mutation in the pi6 gene, which encodes a cyclin-kinase inhibitor that restricts progression through the cell cycle. Such cells can grow for an unlimited time in culture If periodically diluted and supplied with nutrients, which normal cells cannot (see Figure 6-37b). These immortal 3T3 cells are transformed Into full-blown tumor cells only when they produce a constltu-tlvely active Ras protein. For this reason, transfection with the ras gene can transform 3T3 cells, but not normal cultured primary fibroblast cells. Into tumor cells. 

Boulaire, J., Fotedar, A., Fotedar, R. (2000). The functions of the CDK-cyclin kinase inhibitor p21WAFl. Pathologie-biobgie, 48, 190-202. 

The compound sanguinarine inhibited cell proliferation and induced apoptosis in a dose-dependent manner in several lymphoma cell lines (Hussain et al. 2007). Sanguinarine has been shown to inhibit angiogenesis in the membrane of chick embryos (Eun and Koh 2004). In human prostate cancer cell lines, the compound sanguinarine caused cell cycle blockade and apoptosis by modulation of cyclin kinase inhibitor-cyclin-cyclin-dependent kinase machinery (Adhami et al. 2004). 

Sanguinarine causes cell cycle blockade and apoptosis of human prostate carcinoma cells via modulation of cyclin kinase inhibitor-cyclin-cyclin-dejjendent kinase machinery. 

DNA intercalation mutagenic Induction of cyclin kinase inhibitor p21 inhibition of topoisomerase II expression... 

Khleif, S.N., DeGregori, J., Yee, C.L., Otterson, G.A., Kaye, F.J., Nevins, J.R., and Howley, RM. (1996). Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity. Proc. Natl. Acad. Sci. USA 93, 4350-4354. 

---