Protein kinases Checkpoint kinase

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... 

Recent studies have concentrated on control mechanisms, such as the crucial part played by cyclin dependent protein kinases in triggering chromosome duplication and segregation (Nurse 1990) and surveillance mechanisms (checkpoints) that monitor the fidelity of these two processes (Hartwell Weinert 1989). This focus on control is however a recent phenomenon. Earlier studies, largely... 

As might be expected from other mechanisms of regulation described in this text, phosphorylation and dephosphorylation of key proteins is the main mechanism for regulating the cycle, i.e. reversible phosphorylation, also known as interconversion cycles (discussed in Chapter 3). In the cell cycle, several of these interconversion cycles play a role in control at the checkpoints. Two important terms must be appreciated to help understand the mechanism of regulation of the cycle the phosphorylation of proteins is catalysed by specific protein kinases, known as cell-division kinases (cdck) or cell cycle kinases (cck) and these enzymes are activated by specific proteins, known as cyclins. 

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... 

The signaling pathways that lead from the appearance of DNA damage to a halt in the cell cycle include a number of components of which the function has only partially been characterized. So far, it has been estabhshed that the DNA damage checkpoints of different organisms have a common homologous component, namely a protein kinase, which belongs to the superfamUy of P13-kinases (see 6.6). 

Li, Q., Zhu, G.D. (2002) Targeting ser-ine/threonine protein kinase B/Akt and cell-cycle checkpoint kinases for treating cancer. Curr Top Med Chem.2, 939-971. 

The powerful cancer suppressor, p53, which is also described in Box 11-D, in some way senses DNA damage. It prevents passage through the G checkpoint and also through the G2 checkpoint if the DNA has not been adequately repaired.496 497 Protein p53, whose three-dimensional structure is known,500 501 binds to DNA and also induces transcription of genes that cause arrest of the cell cycle. It may also induce cell death (apoptosis), a process that may also require the protein product of protooncogene c-mi/c.502 505 A variety of protein kinases and phosphatases act on p53 and influence its activity.506... 

Recently considerable attention has been focused on the metabolites belonging to bisindolylmaleimides such as staurosporine (28) [12], UCN-01 (29) [13], rebeccamycin (30) [14], which were produced by the family of Streptomyces, Actinomycetes, and Saccharothrixes. These metabolites cause topoisomerase I mediated DNA cleavage, potent inhibition of protein kinase C and cell-cycle-regulating cyclin-dependent kinase (CDK), and cell-cycle checkpoint inhibition [15]. It seems interesting that myxomycetes also contain the bisindole metabolites having related structures to 28 - 30. 

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. 

Biggins S, Murray AW. The budding yeast protein kinase Ipll/ Aurora allows the absence of tension to activate the spindle checkpoint. Genes Dev. 2001 15 3118-3129. 

Other mechanisms of action involve inhibitors of the heat shock protein Hsp-90, of checkpoint kinases, and inhibitors of protein degradation by interaction with the proteasome. 

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.

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