Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of cells with microtubule inhibitors results in activation of the mitotic spindle assembly checkpoint, leading to mitotic arrest before anaphase. Upon prolonged treatment, however, cells can adapt and exit mitosis aberrantly, resulting in the occurrence of tetraploid cells in G1. Those cells subsequently arrest in postmitotic G1 due to the activation of a p53-dependent G1 checkpoint. Failure of the G1 checkpoint leads to endoreduplication and further polyploidization. Using HCT116 and isogenic p53-deficient or spindle checkpoint compromised derivatives, we show here that not only p53 but also a functional spindle assembly checkpoint is required for postmitotic G1 checkpoint function. During transient mitotic arrest, p53 stabilization and activation is triggered by a pathway independent of ATM/ATR, Chk1 and Chk2. We further show that a prolonged spindle checkpoint-mediated mitotic arrest is required for proper postmitotic G1 checkpoint function. In addition, we demonstrate that polyploid cells are inhibited to re-enter mitosis by an additional checkpoint acting in G2. Thus, during a normal cell cycle, polyploidization and subsequent aneuploidization is prevented by the function of the mitotic spindle checkpoint, a p53-dependent G1 checkpoint and an additional G2 checkpoint.
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PMID:Crosstalk of the mitotic spindle assembly checkpoint with p53 to prevent polyploidy. 1528 7

The mammalian mismatch repair (MMR) system has been implicated in activation of the G(2) checkpoint induced by methylating agents. In an attempt to identify the signaling events accompanying this phenomenon, we studied the response of MMR-proficient and -deficient cells to treatment with the methylating agent temozolomide (TMZ). At low TMZ concentrations, MMR-proficient cells were growth-inhibited, arrested in G(2)/M, and proceeded to apoptosis after the second post-treatment cell cycle. These events were accompanied by activation of the ATM and ATR kinases, and phosphorylation of Chk1, Chk2, and p53. ATM was activated later than ATR and was dispensable for phosphorylation of Chk1, Chk2, and p53 on Ser15 and for triggering of the G(2)/M arrest. However, it conferred protection against cell growth inhibition induced by TMZ. ATR was activated earlier than ATM and was required for an efficient phosphorylation of Chk1 and p53 on Ser15. Moreover, abrogation of ATR function attenuated the TMZ-induced G(2)/M arrest and increased drug-induced cytotoxicity. Treatment of MMR-deficient cells with low TMZ concentrations failed to activate ATM and ATR and to cause phosphorylation of Chk1, Chk2, and p53, as well as G(2)/M arrest and apoptosis. However, all these events occurred in MMR-deficient cells exposed to high TMZ concentrations, albeit with faster kinetics. These results demonstrate that TMZ treatment activates ATM- and ATR-dependent signaling pathways and that this process is absolutely dependent on functional MMR only at low drug concentrations.
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PMID:DNA damage induced by temozolomide signals to both ATM and ATR: role of the mismatch repair system. 1532 39

Mammalian Chk1 and Chk2 protein kinases are two important components of the G(2) DNA damage checkpoint. They are activated by upstream kinases (ataxia telangectasia mutated gene and ATM and Rad 3 related gene) and interfere with the activity of the cdc2/cyclinB1 complex, necessary for the G(2)-M transition, through the inactivation of the cdc25 phosphatases (cdc25A and cdc25C). To understand the role of Chk1 and Chk2 in the cellular response to different anticancer agents, we knocked down the expression of each protein or simultaneously of both proteins by using the small interfering RNA technique in the HCT-116 colon carcinoma cell line and in its isogenic systems in which p53 and p21 have been inactivated by targeted homologous recombination. We here show that inhibition of Chk1 but not of Chk2 in p21(-/-) and p53(-/-) cells caused a greater abrogation of G(2) block induced by ionizing radiation and cis-diamine-dichloroplatinum treatments and a greater sensitization to the same treatments than in the parental cell line with p53 and p21 wild type proteins. These data further emphasise the role of Chk1 as a molecular target to inhibit in tumors with a defect in the G(1) checkpoint with the aim of increasing the selectivity and specificity of anticancer drug treatments.
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PMID:Chk1, but not Chk2, is involved in the cellular response to DNA damaging agents: differential activity in cells expressing or not p53. 1532 76

The DNA damage checkpoint kinase, CHK2, promotes growth arrest or apoptosis through phosphorylating targets such as Cdc25A, Cdc25C, BRCA1, and p53. Both germline and somatic loss-of-function CHEK2 mutations occur in human tumours, the former linked to the Li-Fraumeni syndrome, and the latter found in diverse types of sporadic malignancies. Here we examined the status of CHK2 by genetic and immunohistochemical analyses in 53 breast carcinomas previously characterized for TP53 status. We identified two CHEK2 mutants, 470T>C (Ile157Thr), and a novel mutation, 1368insA leading to a premature stop codon in exon 13. The truncated protein encoded by CHEK2 carrying the 1368insA was stable yet mislocalized to the cytoplasm in tumour sections and when ectopically expressed in cultured cells. Unexpectedly, we found CHEK2 to be subject to extensive alternative splicing, with some 90 splice variants detected in our tumour series. While all cancers expressed normal-length CHEK2 mRNA together with the spliced transcripts, we demonstrate and/or predict some of these splice variants to lack CHK2 function and/or localize aberrantly. We conclude that cytoplasmic sequestration may represent a novel mechanism to disable CHK2, and propose to further explore the significance of the complex splicing patterns of this tumour suppressor gene in oncogenesis.
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PMID:Alternative splicing and mutation status of CHEK2 in stage III breast cancer. 1536 33

Bloom's syndrome is a rare autosomal recessive genetic disorder characterized by chromosomal aberrations, genetic instability, and cancer predisposition, all of which may be the result of abnormal signal transduction during DNA damage recognition. Here, we show that BLM is an intermediate responder to stalled DNA replication forks. BLM colocalized and physically interacted with the DNA damage response proteins 53BP1 and H2AX. Although BLM facilitated physical interaction between p53 and 53BP1, 53BP1 was required for efficient accumulation of both BLM and p53 at the sites of stalled replication. The accumulation of BLM/53BP1 foci and the physical interaction between them was independent of gamma-H2AX. The active Chk1 kinase was essential for both the accurate focal colocalization of 53BP1 with BLM and the consequent stabilization of BLM. Once the ATR/Chk1- and 53BP1-mediated signal from replicational stress is received, BLM functions in multiple downstream repair processes, thereby fulfilling its role as a caretaker tumor suppressor.
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PMID:Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest. 1536 58

Gene-environment interactions are implicated in congenital human disorders. Accordingly, there is a pressing need to develop animal models of human disease, which are the product of defined gene-environment interactions. Previously, our laboratory demonstrated that gestational salt stress of bradykinin B(2) receptor (B(2)R)-null mice induces renal dysgenesis and early death of the offspring. In contrast, salt-stressed B(2)R +/+ or +/- littermates have normal development. The present study investigates the mechanisms underlying the susceptibility of B(2)R-null mice to renal dysgenesis. Proteomic and conventional Western blot screens identified E-cadherin among the differentially repressed proteins in B(2)R-/- kidneys, whereas the checkpoint kinase Chk1 and its substrate P-Ser(20) p53 were induced. We tested the hypothesis that p53 mediates repression of E-cadherin gene expression and is causally linked to the renal dysgenesis. Genetic crosses between B(2)R -/- and p53+/- mice revealed that germline reduction of p53 gene dosage rescues B(2)R-/- mice from renal dysgenesis and restores kidney E-cadherin gene expression. Furthermore, gamma-irradiation induces repression of E-cadherin gene expression in p53+/+ but not -/- cells. In transient transfection assays, p53 repressed human E-cadherin promoter-driven reporter activity, whereas a mutant p53, which cannot bind DNA, did not. Functional promoter analysis indicated the presence of a p53-responsive element in exon 1, which partially mediates p53-induced repression. Chromatin immunoprecipitation assays revealed that p53 inhibits histone acetylation of the E-cadherin promoter. Treatment with a histone deacetylase inhibitor reversed both p53-mediated promoter repression and deacetylation. In conclusion, this study demonstrates that gene-environment interactions cooperate to induce congenital defects through p53 activation.
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PMID:A novel pathological role of p53 in kidney development revealed by gene-environment interactions. 1538 1

Chronic myelogenous leukaemia (CML) is induced by the Bcr-Abl fusion protein. Inhibition of Bcr-Abl by STI571 is widely used to treat CML patients. Unlike in most cancer types, the frequency of p53 mutations in CML is low. Here, we investigated the effect of STI571 treatment of CML cells on p53 regulation. Exposure of CML cells, including established cell lines and freshly isolated cells from patients, to STI571 reduced p53 protein levels, and severely impaired its accumulation in response to DNA damage. This may be explained by the status of p53 serine 20 phosphorylation. In non-stressed CML cells, serine 20 of p53 is constitutively phosphorylated by Chk1, and is inhibited by STI571. In response to DNA damage, however, this phosphorylation is mediated by Chk1 and Chk2, and is only partially inhibited by STI571. CML cells expressing wild-type p53 are more resistant to treatment with STI571, but moderately more sensitive to DNA damage, than CML cells lacking p53. An enhanced induction of apoptosis by STI571 and DNA damage is observed in CML cells bearing wild-type p53, but not in cells lacking functional p53. This implies that the status of p53 may affect the response of CML cells to this combined treatment.
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PMID:Treatment of chronic myeloid leukemia cells with imatinib (STI571) impairs p53 accumulation in response to DNA damage. 1546 43

Loss of telomere integrity can have two outcomes with opposite predicted effects on tumorigenesis. On the one hand, shortened telomeres in normal cells may trigger cell cycle arrest, leading to tumor suppression. On the other hand, in a tumor cell in which neither the p53 nor pRb pathway is intact, shortened telomeres could initiate chromosome instability and promote tumorigenesis A major issue in telomere research is to understand how shortened dysfunctional telomeres can regulate the onset of cellular senescence. Recent studies have revealed that critically shortened or acutely uncapped telomeres share molecular features with damaged DNA. We have recently linked the phosphorylation and activation of one major DNA damage effector checkpoint kinase, Chk2, to telomere erosion in signalling cell cycle arrest in normal fibroblasts. Here, we discuss several hypotheses to explain the molecular events occurring at shortened telomeres that ultimately lead to cell cycle arrest or increased genomic instability.
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PMID:Dysfunctional telomeres at senescence signal cell cycle arrest via Chk2. 1546 58

Centrosomes consist of a pair of barrel-shaped microtubule assemblies called centrioles, surrounded by a pericentriolar matrix. The only well-characterized functions of centrosomes is to recognize both interphase microtubule arrays responsible for cell polarity and the mitotic spindle, which mediates the strictly bipolar separations of chromosomes. In addition to these established functions it has been speculated that centrosomes might be involved in several different cell cycle regulatory events like entry into mitosis, cytokinesis, G(1)/S transition and monitoring of DNA damage. These assumptions are mainly based on a rapidly growing list of centrosome-associated regulatory proteins such as p53, Brca1, Chk1, Chk2, TopBP1, Aurora-A, Plk1, cyclin B1, and Cdk1. However, only very few direct links between their localization to the centrosome and specific cellular functions have been unraveled until recently. This review will focus on recent advances in the understanding of the role of centrosomes as integrators of positive and negative pathways for mitotic entry.
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PMID:Checking out the centrosome. 1548 2

Inhibitors of the G(2) DNA damage checkpoint can selectively sensitize cancer cells with mutated p53 to killing by DNA-damaging agents. Isogranulatimide is a G(2) checkpoint inhibitor containing a unique indole/maleimide/imidazole skeleton identified in a phenotypic cell-based screen; however, the mechanism of action of isogranulatimide is unknown. Using natural and synthetic isogranulatimide analogues, we show that the imide nitrogen and a basic nitrogen at position 14 or 15 in the imidazole ring are important for checkpoint inhibition. Isogranulatimide shows structural resemblance to the aglycon of UCN-01, a potent bisindolemaleimide inhibitor of protein kinase C beta (IC(50), 0.001 micromol/L) and of the checkpoint kinase Chk1 (IC(50), 0.007 micromol/L). In vitro kinase assays show that isogranulatimide inhibits Chk1 (IC(50), 0.1 micromol/L) but not protein kinase C beta. Of 13 additional protein kinases tested, isogranulatimide significantly inhibits only glycogen synthase kinase-3beta (IC(50), 0.5 micromol/L). We determined the crystal structure of the Chk1 catalytic domain complexed with isogranulatimide. Like UCN-01, isogranulatimide binds in the ATP-binding pocket of Chk1 and hydrogen bonds with the backbone carbonyl oxygen of Glu(85) and the amide nitrogen of Cys(87). Unlike UCN-01, the basic N15 of isogranulatimide interacts with Glu(17), causing a conformation change in the kinase glycine-rich loop that may contribute importantly to inhibition. The mechanism by which isogranulatimide inhibits Chk1 and its favorable kinase selectivity profile make it a promising candidate for modulating checkpoint responses in tumors for therapeutic benefit.
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PMID:Inhibition of Chk1 by the G2 DNA damage checkpoint inhibitor isogranulatimide. 1548 89


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