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)

Cell cycle checkpoints lead to the inhibition of cell cycle progression following DNA damage. A cell-free system derived from Xenopus eggs has been established that reconstitutes the checkpoint pathway inhibiting DNA replication initiation. DNA containing double-strand breaks inhibits replication initiation in a dose-dependent manner. Upon checkpoint activation, a prereplicative complex is assembled that contains ORC, Cdc6, Cdc7, and MCM proteins but lacks Cdc45. The checkpoint is ATM dependent. Cdk2/CyclinE acts downstream of ATM and is downregulated by Cdk2 phosphorylation on tyrosine 15. Cdk2AF/CyclinE is refractory to checkpoint signaling, and Cdc25A overrides the checkpoint and restores DNA replication. This report provides the description of a DNA damage checkpoint pathway that prevents the onset of S phase independently of the transcriptional function of p53 in a vertebrate organism.
 ...
PMID:Reconstitution of an ATM-dependent checkpoint that inhibits chromosomal DNA replication following DNA damage. 1103 Mar 44

p53 plays a central role in the cellular response to DNA double-strand breaks (DSBs), and to DNA damage in general. The protein kinases ATM, ATR and DNA-PK detect DSBs and transmit this information to p53 by phosphorylation. This phosphorylation dissociates p53 from its negative regulator, mdm2. p53 then undergoes further modification and activates transcription of the genes responsible for cell cycle arrest. In certain circumstances, p53 also activates transcription of the genes responsible for apoptosis. The dysfunction of this cascade of events is oncogenic, with P53 itself being the most commonly mutated gene in malignant cells, although mutations in both the DNA damage sensors and cell cycle checkpoint and apoptosis effectors are frequent. A more complete understanding of p53 and the proteins it interacts with may allow the development of new cancer treatments.
 ...
PMID:[p53 activation by PI-3K family kinases after DNA double-strand breaks]. 1103 13

In a screen designed to discover suppressors of mitotic catastrophe, we identified the Xenopus ortholog of 53BP1 (X53BP1), a BRCT protein previously identified in humans through its ability to bind the p53 tumor suppressor. X53BP1 transcripts are highly expressed in ovaries, and the protein interacts with Xp53 throughout the cell cycle in embryonic extracts. However, no interaction between X53BP1 and Xp53 can be detected in somatic cells, suggesting that the association between the two proteins may be developmentally regulated. X53BP1 is modified via phosphorylation in a DNA damage-dependent manner that correlates with the dispersal of X53BP1 into multiple foci throughout the nucleus in somatic cells. Thus, X53BP1 can be classified as a novel participant in the DNA damage response pathway. We demonstrate that X53BP1 and its human ortholog can serve as good substrates in vitro as well as in vivo for the ATM kinase. Collectively, our results reveal that 53BP1 plays an important role in the checkpoint response to DNA damage, possibly in collaboration with ATM.
 ...
PMID:Negative cell cycle regulation and DNA damage-inducible phosphorylation of the BRCT protein 53BP1. 1104 16

The integrity of the DNA damage response pathway is essential for prevention of neoplastic transformation. Several proteins involved in this pathway including p53, BRCA1, and ATM are frequently mutated in human cancer. Checkpoint kinase 2 (Chk2) is a DNA damage-activated protein kinase that lies downstream of ATM in this pathway. Recently, heterozygous germline mutations in Chk2 have been identified in a subset of patients with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype, suggesting that Chk2 is a tumor suppressor gene. In this study, we have reported the biochemical characterization of the four tumor-associated Chk2 mutants. Two of the reported Chk2 mutations identified in Li-Fraumeni syndrome result in loss of Chk2 kinase activity. Whereas one mutation within the Chk2 forkhead homology-associated (FHA) domain, R145W, retains some basal kinase activity, this mutant cannot be phosphorylated at an ATM-dependent phosphorylation site (Thr-68) and cannot be activated following gamma radiation. Wild-type Chk2 exists mainly in a protein complex of M(r) approximately 200,000 whereas the R145W mutant forms a larger, presumably inactive complex in the cell. The other FHA domain mutant, I157T, behaves as wild-type Chk2 in all the assays used here. Because the FHA domain is involved in protein-protein interactions, this mutation may affect associations of Chk2 with other proteins. Additionally, we have shown that Chk2 can also be inactivated by down-regulation of its expression in cancer cells. Thus, Chk2 may be inactivated by multiple mechanisms in the cell.
 ...
PMID:Characterization of tumor-associated Chk2 mutations. 1105 50

Genistein is an isoflavenoid that is abundant in soy beans. Genistein has been reported to have a wide range of biological activities and to play a role in the diminished incidence of breast cancer in populations that consume a soy-rich diet. Genistein was originally identified as an inhibitor of tyrosine kinases; however, it also inhibits topoisomerase II by stabilizing the covalent DNA cleavage complex, an event predicted to cause DNA damage. The topoisomerase II inhibitor etoposide acts in a similar manner. Here we show that genistein induces the up-regulation of p53 protein, phosphorylation of p53 at serine 15, activation of the sequence-specific DNA binding properties of p53, and phosphorylation of the hCds1/Chk2 protein kinase at threonine 68. Phosphorylation and activation of p53 and phosphorylation of Chk2 were not observed in ATM-deficient cells. In contrast, the topoisomerase II inhibitor etoposide induced phosphorylation of p53 and Chk2 in ATM-positive and ATM-deficient cells. In addition, genistein-treated ATM-deficient cells were significantly more susceptible to genistein-induced killing than were ATM-positive cells. Together our data suggest that ATM is required for activation of a DNA damage-induced pathway that activates p53 and Chk2 in response to genistein.
 ...
PMID:The plant isoflavenoid genistein activates p53 and Chk2 in an ATM-dependent manner. 1109 68

The c-abl proto-oncogene encodes a protein tyrosine kinase that is distributed in the nucleus and the cytoplasm of proliferating cells. In the nucleus, c-Abl activity is negatively regulated by the retinoblastoma protein (RB) and positively regulated by DNA damage signals. Activation of the c-Abl kinase by DNA damage requires the function of ATM, which regulates cell cycle checkpoint, DNA repair and apoptosis in response to DNA damage. Cells lacking c-Abl can activate cell cycle checkpoints and DNA repair, but show defects in apoptosis. The apoptosis defect of c-Abl deficient cells is correlated with a defect in the induction and activation of p73, which is a functional homologue of the p53 tumor suppressor protein and has pro-apoptotic activity. The inhibition of c-Abl by RB is consistent with RB's ability to block apoptosis; while the activation of c-Abl by ATM is consistent with ATM's ability to activate cell death. The oncogenic Bcr-Abl tyrosine kinase is a potent inhibitor of apoptosis, and it is retained exclusively in the cytoplasm of transformed cells. Interestingly, when Bcr-Abl is trapped inside of the nucleus through a combined disruption of its cytoplasmic retention and its nuclear export, this oncogenic Abl kinase induces apoptosis. Taken together, the current results support a role for the nuclear c-Abl tyrosine kinase in the regulation of apoptosis. Whether the cytoplasmic c-Abl kinase can actively inhibit apoptosis remains to be determined; however, a deliberate retention of c-Abl in the cytoplasm could potentially contribute to the attenuation of apoptosis response.
 ...
PMID:Regulation of cell death by the Abl tyrosine kinase. 1111 45

Recent evidence from several investigators suggest that the human T-cell leukemia virus type 1 Tax oncoprotein represses the transcriptional activity of the tumor suppressor protein, p53. An examination of published findings reveals serious controversy as to the mechanism(s) utilized by Tax to inhibit p53 activity and whether the same mechanism is used by Tax in adherent and suspension cells. Here, we have investigated Tax-p53 interaction simultaneously in adherent epithelial (HeLa and Saos) and suspension T-lymphocyte (Jurkat) cells. Our results indicate that Tax activity through the CREB/CREB-binding protein (CBP), but not NF-kappaB, pathway is needed to repress the transcriptional activity of p53 in all tested cell lines. However, we did find that while CBP binding by Tax is necessary, it is not sufficient for inhibiting p53 function. Based on knockout cell studies, we correlated a strong genetic requirement for the ATM, but not protein kinase-dependent DNA, protein in conferring a Tax-p53-repressive phenotype.
 ...
PMID:Genetic evidence of a role for ATM in functional interaction between human T-cell leukemia virus type 1 Tax and p53. 1111 8

Bloom's syndrome (BS), a rare genetic disease, arises through mutations in both alleles of the BLM gene which encodes a 3'-5' DNA helicase identified as a member of the RecQ family. BS patients exhibit a high predisposition to development of all types of cancer affecting the general population and BLM-deficient cells display a strong genetic instability. We recently showed that BLM protein expression is regulated during the cell cycle, accumulating to high levels in S phase, persisting in G2/M and sharply declining in G1, suggesting a possible implication of BLM in a replication (S phase) and/or post-replication (G2 phase) process. Here we show that, in response to ionizing radiation, BLM-deficient cells exhibit a normal p53 response as well as an intact G1/S cell cycle checkpoint, which indicates that ATM and p53 pathways are functional in BS cells. We also show that the BLM defect is associated with a partial escape of cells from the gamma-irradiation-induced G2/M cell cycle checkpoint. Finally, we present data demonstrating that, in response to ionizing radiation, BLM protein is phosphorylated and accumulates through an ATM-dependent pathway. Altogether, our data indicate that BLM participates in the cellular response to ionizing radiation by acting as an ATM kinase downstream effector.
 ...
PMID:ATM-dependent phosphorylation and accumulation of endogenous BLM protein in response to ionizing radiation. 1114 46

p53 is required for the induction of a G(1) and/or G(2) irreversible arrest after gamma irradiation (IR), whereas blocked DNA replication causes a p53-independent S-phase arrest. We have examined the response to p53 when DNA synthesis is blocked by hydroxyurea (HU) or aphidicolin or when DNA is damaged by gamma IR. Similarly to gamma IR, blocked DNA synthesis induces high levels of phosphorylated nuclear p53. Surprisingly, several (but not all) p53 transcriptional targets that are rapidly induced by gamma IR are weakly or not induced when DNA replication is blocked. Moreover, the p53 response to gamma IR is inhibited by pretreatment of cells with HU or aphidicolin, suggesting that blocked DNA replication prevents p53 from being fully active as a transcription factor. HU-induced stabilization of p53 neither requires functional ATM (ataxia telangiectasia mutated), nor interferes with the gamma IR-dependent activation of the ATM kinase. Thus, stalled replication forks activate kinases that modify and stabilize p53, yet act downstream of ATM to impair p53 transcriptional activity. The ramifications of this novel regulation of p53 are discussed.
 ...
PMID:p53 accumulates but is functionally impaired when DNA synthesis is blocked. 1115 42

To further understand the mechanism(s) by which DNA damage activates p53, we analysed the expression levels of p53 and HDM2 (the human homolog of murine MDM2) in various human diploid fibroblast and tumor cell strains during the period that precedes activation of known downstream effectors of p53. In X-irradiated human cells, HDM2 protein was rapidly phosphorylated in serine/threonine residues in a p53, p14ARF and p73-independent manner. In p53 wild-type cells, HDM2 phosphorylation precedes a detectable increase in the levels of p53 and is not observed in ataxia telangiectasia (AT) fibroblasts. The transfection of AT cells with a vector expressing ATM restored the ability to rapidly phosphorylate HDM2 following X-irradiation, confirming a role for ATM in its phosphorylation. We also show that ATM complexes with HDM2. The DNA lesions signaling the early rapid phosphorylation of HDM2 are a result of X-ray and not UV-type damage. The ATM-promoted early covalent modification of HDM2 in X-irradiated human cells may provide a mechanism to activate p53.
 ...
PMID:ATM complexes with HDM2 and promotes its rapid phosphorylation in a p53-independent manner in normal and tumor human cells exposed to ionizing radiation. 1117 32


<< Previous 1 2 3 4 5 6 7 8 9 10