Chkl/2 protein kinases

Gravest PR, Yu L, Schwartz JK, Gales J, Sausville EA, et al. 2000. The Chkl protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01. J.Biol. Chem. 275 5600-5... 

Cells that fail to replicate all their chromosomes do not enter mitosis. Operation of the unrepIicated-DNA checkpoint control involves the recognition of unreplicated DNA and inhibition of MPF activation (see Figure 21-32, [T]). Recent genetic studies in 5. pombe and biochemical studies with Xenopus egg extracts suggest that the ATR and Chkl protein kinases, which also function in the DNA-damage checkpoint, inhibit entry into mitosis by cells that have not completed DNA synthesis. 

Walworth, N., Davey, S., and Beach, D. (1993). Fission yeast chkl protein kinase links the rad checkpoint pathway to cdc2. Nature 363, 368-371. 

Sanchez Y, Bachant J, Wang H et al 1999 Control of the DNA damage checkpoint by chkl and rad53 protein kinases through distinct mechanisms. Science 286 1166-1171... 

Hymenialdisins proved to be nanomolar inhibitors of G2 DNA damage checkpoint and of the protein kinases Chkl and Chk2 [56], mitogen-activated protein kinase 1 (MEK-1) [57], and of other kinases [58[ therefore, they could be valuable agents in cancer therapy. In addition, hymenialdisins have been show n to inhibit... 

N. C. Vihlworth and R Bernards. Rad-dependent response of the chkl-encoded protein kinase at the DNA damage checkpoint [see comments]. Science, 271 (5247), 353-356, 1996. 

Fig. 13.19 The Gt DNA damage checkpoint. DNA damage induces activation of the protein kinases ATM and ATR via reactions not illustrated in the figure. ATM and ATR phosphorylate and activate the protein kinases Chkl and Chk2 which phosphorylate and inactivate the protein phosphatase CDC25A. This phosphatase is required for removal of the inhibitory phosphorylations on T14 and Y15 of CDK2 and hence for G S-phase progression. CDC25A phosphorylation mediates ubiquitination and proteasomal degradation ofCDC25A. As a consequence, CDK2 retains its inhibitory phosphorylations and the cell arrests in Gl.

BRCA1 is essential for activating the protein kinase Chkl that regulates DNA da-mage-induced G2/M arrest (review Yarden et al., 2002). 

The association of ATR with replication forks is thought to activate its protein kinase activity, leading to the phosphorylation and activation of the Chkl kinase. Active Chkl then phosphorylates and inactivates the Cdc25 phosphatase (Cdc25C in vertebrates), which normally removes the inhibitory phosphate from CDKs that function during mitosis. As a result, the cyclln A/B-CDKl complexes remain inhibited and cannot phosphorylate targets required to initiate mitosis. ATR continues to initiate this protein kinase cascade until all replication forks complete DNA replication and disassemble. 

The selective Pim-l kinase inhibitor quercetagetin was shown to be the most potent synapsin I binder (IC50 = 0.15 ]liM), in agreement with the predicted binding site similarities between synapsin I and various protein kinases. Other protein kinase inhibitors (protein kinase A and chkl inhibitor), kinase inhibitors (diacylglycerol kinase inhibitor), and various other ATP competitors (DNA topoisomerase II and HSP-90a inhibitors) did not bind to synapsin I, as predicted from a lower similarity of their respective ATP-binding sites to that of synapsin I (Figure 6.7). 

Cole KA, Huggins J, Laquaglia M et al (2011) RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHKl) as a therapeutic target in neuroblastoma. Proc Natl Acad Sci USA 108 3336-3341... 

Key words PGVL Hub, combinatorial chemistry, library design, reaction, synthesis protocol, reactant, product, enumeration, filtering, Chkl, kinase, inhibitor, SAR, ADME T (Adsorption, Distribution, Metabolism, Excretion, and Toxicity), selectivity, solubility, protein-ligand complex. 

Fig. 16.2. Cell cycle, Chkl at the G2/M checkpoint, and key structural features of the Chkl kinase domain (4a). The highlighted location is the hinge region of the Chkl kinase domain, which also corresponds to the same regions of protein-ligand structures shown in Fig. 16.1.

Resveratrol exerts antitumor effects partly by arresting the growth of various cancer cells in culture [Kundu and Surh, 2004]. The inhibition of ornithine decarboxylase (ODC), a biochemical hallmark of tumor promotion, has been shown to account for the antiproliferative and antitumor effects of resveratrol [Schneider et al., 2000 Ulrich et al., 2007]. Aberrant changes in cell-cycle machinery are considered as the biochemical basis of abnormal proliferation of transformed cells. Major cell-cycle regulatory proteins include various cyclins, cyclin-dependent kinases (Cdk), Cdk inhibitors, and check point kinases (Chkl... 

Arrest in Gx phase can now be achieved in at least two ways, depending on the substrates of the Chkl and Chk2 enzymes. In one rapid way, the dual specificity phosphatase Cdc25C is phosphorylated on Ser 123 and is thereby targeted for ubiquitina-tion and degradation in the proteasome pathway. The lack of this enzyme locks the CDK2 kinase in the inactive form phosphorylated on threonine 14 and tyrosine 15.The cyclin E-CDK2 complex that is required for entry into S phase is inhibited, and the cell cycle arrests at Gj/S. It should be noted that the scheme in Fig. 13.19 is only a minimal scheme that does not address the participation of numerous other proteins that function as adaptors or structural proteins in these processes. 

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