Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fanconi anemia (FA), a rare inherited disorder, exhibits a complex phenotype including progressive bone marrow failure, congenital malformations and increased risk of cancers, mainly acute myeloid leukaemia. At the cellular level, FA is characterized by hypersensitivity to DNA cross-linking agents and by high frequencies of induced chromosomal aberrations, a property used for diagnosis. FA results from mutations in one of the eleven FANC (FANCA to FANCJ) genes. Nine of them have been identified. In addition, FANCD1 gene has been shown to be identical to BRCA2, one of the two breast cancer susceptibility genes. Seven of the FANC proteins form a complex, which exists in four different forms depending of its subcellular localisation. Four FANC proteins (D1(BRCA2), D2, I and J) are not associated to the complex. The presence of the nuclear form of the FA core complex is necessary for the mono-ubiquitinylation of FANCD2 protein, a modification required for its re-localization to nuclear foci, likely to be sites of DNA repair. A clue towards understanding the molecular function of the FANC genes comes from the recently identified connection of FANC to the BRCA1, ATM, NBS1 and ATR genes. Two of the FANC proteins (A and D2) directly interact with BRCA1, which in turn interacts with the MRE11/RAD50/NBS1 complex, which is one of the key components in the mechanisms involved in the cellular response to DNA double strand breaks (DSB). Moreover, ATM, a protein kinase that plays a central role in the network of DSB signalling, phosphorylates in vitro and in vivo FANCD2 in response to ionising radiations. Moreover, the NBS1 protein and the monoubiquitinated form of FANCD2 seem to act together in response to DNA crosslinking agents. Taken together with the previously reported impaired DSB and DNA interstrand crosslinks repair in FA cells, the connection of FANC genes to the ATM, ATR, NBS1 and BRCA1 links the FANC genes function to the finely orchestrated network involved in the sensing, signalling and repair of DNA replication-blocking lesions.
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PMID:[Fanconi anemia: genes and function(s) revisited]. 1611 58

Replication protein A (RPA) is the major single-stranded DNA-binding protein in eukaryotes, essential for DNA replication, repair, and recombination. During mitosis and meiosis in budding yeast, RPA becomes phosphorylated in reactions that require the Mec1 protein kinase, a central checkpoint regulator and homolog of human ATR. Through mass spectrometry and site-directed mutagenesis, we have now identified a single serine residue in the middle subunit of the RPA heterotrimer that is targeted for phosphorylation by Mec1 both in vivo and in vitro. Cells containing a phosphomimetic version of RPA generated by mutation of this serine to aspartate exhibit a significant alteration in the pattern of meiotic crossovers for specific genetic intervals. These results suggest a new function of Mec1 that operates through RPA to locally control reciprocal recombination.
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PMID:Evidence of meiotic crossover control in Saccharomyces cerevisiae through Mec1-mediated phosphorylation of replication protein A. 1611 84

Claspin is required for the phosphorylation and activation of the Chk1 protein kinase by ATR during DNA replication and in response to DNA damage. This checkpoint pathway plays a critical role in the resistance of cells to genotoxic stress. Here, we show that human Claspin is cleaved by caspase-7 during the initiation of apoptosis. In cells, induction of DNA damage by etoposide at first produced rapid phosphorylation of Chk1 at a site targeted by ATR. Subsequently, etoposide caused activation of caspase-7, cleavage of Claspin, and dephosphorylation of Chk1. In apoptotic cell extracts, Claspin was cleaved by caspase-7 at a single aspartate residue into a large N-terminal fragment and a smaller C-terminal fragment that contain different functional domains. The large N-terminal fragment was heavily phosphorylated in a human cell-free system in response to double-stranded DNA oligonucleotides, and this fragment retained Chk1 binding activity. In contrast, the smaller C-terminal fragment did not bind Chk1, but did associate with DNA and inhibited the DNA-dependent phosphorylation of Chk1 associated with its activation. These results indicate that cleavage of Claspin by caspase-7 inactivates the Chk1 signaling pathway. This mechanism may regulate the balance between cell cycle arrest and induction of apoptosis during the response to genotoxic stress.
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PMID:Cleavage of claspin by caspase-7 during apoptosis inhibits the Chk1 pathway. 1612 41

The replication checkpoint monitors the progress of DNA replication forks during S phase, and delays the firing of later replication origins when active replication forks are stalled due to collisions with damaged or abnormally structured DNA. Key components of the replication checkpoint pathway are the apical protein kinase, ATR, and its downstream target kinase, Chk1. Defects in either ATR or Chk1 function result in loss of DNA replication fidelity and cell viability, even in the absence of extrinsic genotoxic stress. Moreover, several clinically important antitumor agents, such as the camptothecins (CPTs), exert their antitumor effects by interfering with DNA replication, and hence the therapeutic response to these drugs is intimately related to signaling through the replication checkpoint. A recent report from this laboratory adds a new facet to the regulatory mechanisms that control the function and duration of checkpoint signaling through the ATR-Chk1 pathway. The results indicate that replication stress induced by a variety of agents, including CPT and deep hypoxia, triggers the ubiquitin-dependent degradation of the checkpoint kinase Chk1 in both normal and transformed human cells. This review provides an overview of the study's major findings, together with their implications for both replication checkpoint function and tumor responsiveness to CPT and related anticancer drugs.
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PMID:Turning the replication checkpoint on and off. 1635 41

Chk1 is phosphorylated at Ser317 and Ser345 by ATR in response to stalled replication and genotoxic stresses. This Chk1 activation is thought to play critical roles in the prevention of premature mitosis. However, the behavior of Chk1 in mitosis remains largely unknown. Here we reported that Chk1 was phosphorylated in mitosis. The reduction of this phosphorylation was observed at the metaphase-anaphase transition. Two-dimensional phosphopeptide mapping revealed that Chk1 phosphorylation sites in vivo were completely overlapped with the in vitro sites by cyclin-dependent protein kinase (Cdk) 1 or by p38 MAP kinase. Ser286 and Ser301 were identified as novel phosphorylation sites on Chk1. Treatment with Cdk inhibitor butyrolactone I induced the reduction of Chk1-S301 phosphorylation, although treatment with p38-specific inhibitor SB203580 or siRNA did not. In addition, ionizing radiation (IR) or ultraviolet (UV) light did not induce Chk1 phosphorylation at Ser317 and Ser345 in nocodazole-arrested mitotic cells. These observations imply the regulation of mitotic Chk1 function through Chk1 phosphorylation at novel sites by Cdk1.
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PMID:Regulation of mitotic function of Chk1 through phosphorylation at novel sites by cyclin-dependent kinase 1 (Cdk1). 1662

Cisplatin induces renal cell injury and death, resulting in nephrotoxicity that limits its use in cancer therapy. Using cell culture models, recent work has suggested the involvement of p53 in renal cell apoptosis during cisplatin treatment. However, the signals upstream of p53 remain elusive. ATM and ATR are critical regulators of p53 under various conditions of DNA damage. Here, we show that ATM, and not ATR, was proteolytically cleaved into specific fragments of approximately 210 and 150 kDa during cisplatin-induced tubular cell apoptosis. ATM cleavage was paralleled by the development of apoptosis. VAD, a broad-spectrum inhibitor of caspases, attenuated the cleavage of ATM, whereas the inhibitors of specific caspases were less effective. In caspase-3-deficient MCF-7 cells, ATM was cleaved, releasing the 210- but not the 150-kDa fragment. Recombinant caspase-3 was much more effective than caspase-7 in cleaving ATM that was immunoprecipitated from cell lysates. During cisplatin incubation, VAD protected ATM and enhanced p53 phosphorylation. In vitro assay of protein kinase activity further showed that ATM immunoprecipitated from cisplatin-treated cells had significantly lower kinase activity toward p53 than that from control cells. Importantly, the protein kinase activity was restored in ATM that was protected by VAD during cisplatin incubation. ATM deficiency sensitized the cells to cisplatin-induced apoptosis, suggesting a cytoprotective role of ATM in this experimental model. Thus proteolysis of ATM by caspases may inactivate this regulatory molecule to facilitate the progression of apoptosis.
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PMID:Caspase-mediated cleavage of ATM during cisplatin-induced tubular cell apoptosis: inactivation of its kinase activity toward p53. 1684 90

The POT1/TEBP telomere proteins are a group of single-stranded DNA (ssDNA)-binding proteins that have long been assumed to protect the G overhang on the telomeric 3' strand. We have found that the Tetrahymena thermophila genome contains two POT1 gene homologs, POT1a and POT1b. The POT1a gene is essential, but POT1b is not. We have generated a conditional POT1a cell line and shown that POT1a depletion results in a monster cell phenotype and growth arrest. However, G-overhang structure is essentially unchanged, indicating that POT1a is not required for overhang protection. In contrast, POT1a is required for telomere length regulation. After POT1a depletion, most telomeres elongate by 400 to 500 bp, but some increase by up to 10 kb. This elongation occurs in the absence of further cell division. The growth arrest caused by POT1a depletion can be reversed by reexpression of POT1a or addition of caffeine. Thus, POT1a is required to prevent a cell cycle checkpoint that is most likely mediated by ATM or ATR (ATM and ATR are protein kinases of the PI-3 protein kinase-like family). Our findings indicate that the essential function of POT1a is to prevent a catastrophic DNA damage response. This response may be activated when nontelomeric ssDNA-binding proteins bind and protect the G overhang.
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PMID:Tetrahymena POT1a regulates telomere length and prevents activation of a cell cycle checkpoint. 1715 24

Yeast Mec1/Ddc2 protein kinase, the ortholog of human ATR/ATRIP, plays a central role in the DNA damage checkpoint. The PCNA-like clamp Rad17/Mec3/Ddc1 (the 9-1-1 complex in human) and its loader Rad24-RFC are also essential components of this signal transduction pathway. Here we have studied the role of the clamp in regulating Mec1, and we delineate how the signal generated by DNA lesions is transduced to the Rad53 effector kinase. The checkpoint clamp greatly activates the kinase activity of Mec1, but only if the clamp is appropriately loaded upon partial duplex DNA. Activated Mec1 phosphorylates the Ddc1 and Mec3 subunits of the clamp, the Rad24 subunit of the loader, and the Rpa1 and Rpa2 subunits of RPA. Phosphorylation of Rad53, and of human PHAS-1, a nonspecific target, also requires a properly loaded clamp. Phosphorylation and binding studies with individual clamp subunits indicate that the Ddc1 subunit mediates the functional interactions with Mec1.
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PMID:The checkpoint clamp activates Mec1 kinase during initiation of the DNA damage checkpoint. 1718 91

Phosphatidylinositol 3-kinase-related kinases (PIKKs) consisting of SMG-1, ATM, ATR, DNA-PKcs, and mTOR are a family of proteins involved in the surveillance of gene expression in eukaryotic cells. They are involved in mechanisms responsible for genome stability, mRNA quality, and translation. They share a large N-terminal domain and a C-terminal FATC domain in addition to the unique serine/threonine protein kinase (PIKK) domain that is different from classical protein kinases. However, structure-function relationships of PIKKs remain unclear. Here we have focused on one of the PIKK members, SMG-1, which is involved in RNA surveillance, termed nonsense-mediated mRNA decay (NMD), to analyze the roles of conserved and SMG-1-specific sequences on the intrinsic kinase activity. Analyses of sets of point and deletion mutants of SMG-1 in a purified system and intact cells revealed that the long N-terminal region and the conserved leucine in the FATC domain were essential for SMG-1 kinase activity. However, the conserved tryptophan in the TOR SMG-1 (TS) homology domain and the FATC domain was not. In addition, the long insertion region between PIKK and FATC domains was not essential for SMG-1 kinase activity. These results indicated an unexpected feature of SMG-1, i.e. that distantly located N- and C-terminal sequences were essential for the intrinsic kinase activity.
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PMID:Distant N- and C-terminal domains are required for intrinsic kinase activity of SMG-1, a critical component of nonsense-mediated mRNA decay. 1722 28

Progression of the cells through the S phase of the cell cycle is connected with accumulation of stalled and collapsed replication forks that are repaired by homologous recombination. To investigate the temporal order of homologous recombination events during the S phase, HeLa cells synchronized at the G1/S phase boundary with mimosine were released to progress into the S phase and the phosphorylation of the histone variant H2AX, the appearance of Rad51 nuclear foci and the subcellular redistribution of Rad51 were followed. The results showed that there was gradual accumulation of double-strand breaks as judged by the increase in the phosphorylation of H2AX during the S phase. Rad51 nuclear foci did not appear until middle S phase, and this was accompanied by an increase in the chromatin- and nuclear matrix-bound Rad51 in the middle to late S phase. To determine the role of the intra S phase checkpoint in the S phase-dependent redistribution of Rad51 the cells were released in the S phase in the presence of the protein kinase inhibitors caffeine and wortmannin. The results suggest that the association of Rad51 with the nuclear matrix is regulated by activation of the intra S phase ATR-dependent checkpoint pathway.
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PMID:Cell cycle-dependent association of Rad51 with the nuclear matrix. 1726 95


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