Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 protein plays a central role in the integration of cellular stress responses. If the cell incurs DNA damage, p53-induced cell cycle arrest is accompanied by p53-facilitated DNA repair. In particular, p53 has been demonstrated to promote both nucleotide excision repair (NER) and base excision repair (BER). Once these repair processes are completed, p53 activity declines and the cell can reenter the cell cycle. A critical mediator of this p53 negative regulatory feedback loop is Mdm2, a p53 transcriptional target whose protein mediates p53 proteolytic degradation. Another such p53 transcriptional target that may function in a p53 negative regulation is the PPM1D phosphatase. PPM1D may inhibit p53 activity through inactivating dephosphorylation of the p38 MAP kinase. We have recently shown that PPM1D suppresses BER in part through dephosphorylation of a key BER effector, the nuclear isoform of uracil DNA glycosylase, or UNG2. This finding further links p53 signaling to DNA repair pathways and illustrates a mechanism by which activated DNA repair systems are returned to a deactivated, homeostatic state.
...
PMID:Homeostatic regulation of base excision repair by a p53-induced phosphatase: linking stress response pathways with DNA repair proteins. 1553 43

The serine/threonine protein kinase ATM signals to cell cycle and DNA repair components by phosphorylating downstream targets such as p53, CHK2, NBS1, and BRCA1. Mutation of ATM occurs in the human autosomal recessive disorder ataxia-telangiectasia, which is characterized by hypersensitivity to ionizing radiation and a failure of cells to arrest the cell cycle after the induction of DNA double-strand breaks. It has thus been proposed that ATM inhibition would cause cellular radio- and chemosensitization. Through screening a small molecule compound library developed for the phosphatidylinositol 3'-kinase-like kinase family, we identified an ATP-competitive inhibitor, 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one (KU-55933), that inhibits ATM with an IC(50) of 13 nmol/L and a Ki of 2.2 nmol/L. KU-55933 shows specificity with respect to inhibition of other phosphatidylinositol 3'-kinase-like kinases. Cellular inhibition of ATM by KU-55933 was demonstrated by the ablation of ionizing radiation-dependent phosphorylation of a range of ATM targets, including p53, gammaH2AX, NBS1, and SMC1. KU-55933 did not show inhibition of UV light DNA damage induced cellular phosphorylation events. Exposure of cells to KU-55933 resulted in a significant sensitization to the cytotoxic effects of ionizing radiation and to the DNA double-strand break-inducing chemotherapeutic agents, etoposide, doxorubicin, and camptothecin. Inhibition of ATM by KU-55933 also caused a loss of ionizing radiation-induced cell cycle arrest. By contrast, KU-55933 did not potentiate the cytotoxic effects of ionizing radiation on ataxia-telangiectasia cells, nor did it affect their cell cycle profile after DNA damage. We conclude that KU-55933 is a novel, specific, and potent inhibitor of the ATM kinase.
...
PMID:Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. 1560 86

CHK2/hCds1 plays important roles in the DNA damage-induced cell cycle checkpoint by phosphorylating several important targets, such as Cdc25 and p53. To obtain a better understanding of the CHK2 signaling pathway, we have carried out a yeast two-hybrid screen to search for potential CHK2-interacting proteins. Here, we report the identification of the mitotic checkpoint kinase, TTK/hMps1, as a novel CHK2-interacting protein. TTK/hMps1 directly phosphorylates CHK2 on Thr-68 in vitro. Expression of a TTK kinase-dead mutant, TTK(D647A), interferes with the G(2)/M arrest induced by either ionizing radiation or UV light. Interestingly, induction of CHK2 Thr-68 phosphorylation and of several downstream events, such as cyclin B1 accumulation and Cdc2 Tyr-15 phosphorylation, is also affected. Furthermore, ablation of TTK expression using small interfering RNA results not only in reduced CHK2 Thr-68 phosphorylation, but also in impaired growth arrest. Our results are consistent with a model in which TTK functions upstream from CHK2 in response to DNA damage and suggest possible cross-talk between the spindle assembly checkpoint and the DNA damage checkpoint.
...
PMID:TTK/hMps1 participates in the regulation of DNA damage checkpoint response by phosphorylating CHK2 on threonine 68. 1561 21

The ATM protein kinase regulates the response of the cell to DNA damage by associating with and then phosphorylating proteins involved in cell cycle checkpoints and DNA repair. Here, we report on deletion studies designed to identify protein domains required for ATM to phosphorylate target proteins and to control cell survival following exposure to ionizing radiation. Deletion studies demonstrated that amino acids 1-150 of ATM were required for the ATM protein to regulate cellular radiosensitivity. Additional deletions and point mutations indicated that this domain extended from amino acids 81-106 of ATM, with amino acid substitutions located between amino acids 91 and 97 inactivating the functional activity of ATM. When ATM with mutations in this region (termed ATM90) was expressed in AT cells, it was unable to restore normal radiosensitivity to the cells. However, ATM90 retained normal kinase activity and was autophosphorylated on serine 1981 following exposure to DNA damage. Furthermore, wild-type ATM displayed DNA-damage induced association with p53, brca1, and LKB1 in vivo, whereas ATM90 failed to form productive complexes with these target proteins either in vivo or in vitro. Furthermore, ATM90 did not phosphorylate p53 in vivo and did not form nuclear foci in response to ionizing radiation. We propose that amino acids 91-97 of ATM contain a protein interaction domain required for the DNA damage-induced association between ATM and its target proteins, including the brca1, p53, and LKB1 proteins. Furthermore, this domain of ATM is required for ATM to form nuclear foci following exposure to ionizing radiation.
...
PMID:DNA damage-induced association of ATM with its target proteins requires a protein interaction domain in the N terminus of ATM. 1571 74

The ataxia-telangiectasia mutated (ATM) kinase signals the presence of DNA double-strand breaks in mammalian cells by phosphorylating proteins that initiate cell-cycle arrest, apoptosis, and DNA repair. We show that the Mre11-Rad50-Nbs1 (MRN) complex acts as a double-strand break sensor for ATM and recruits ATM to broken DNA molecules. Inactive ATM dimers were activated in vitro with DNA in the presence of MRN, leading to phosphorylation of the downstream cellular targets p53 and Chk2. ATM autophosphorylation was not required for monomerization of ATM by MRN. The unwinding of DNA ends by MRN was essential for ATM stimulation, which is consistent with the central role of single-stranded DNA as an evolutionarily conserved signal for DNA damage.
...
PMID:ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. 1584 43

The ATM (ataxia-telangiectasia mutated) and ATR (ataxia-telangiectasia and Rad3-related) kinases respond to DNA damage by phosphorylating cellular target proteins that activate DNA repair pathways and cell cycle checkpoints in order to maintain genomic integrity. Here we show that the oncogenic p53-induced serine/threonine phosphatase, PPM1D (or Wip1), dephosphorylates two ATM/ATR targets, Chk1 and p53. PPM1D binds Chk1 and dephosphorylates the ATR-targeted phospho-Ser 345, leading to decreased Chk1 kinase activity. PPM1D also dephosphorylates p53 at phospho-Ser 15. PPM1D dephosphorylations are correlated with reduced cellular intra-S and G2/M checkpoint activity in response to DNA damage induced by ultraviolet and ionizing radiation. Thus, a primary function of PPM1D may be to reverse the p53 and Chk1-induced DNA damage and cell cycle checkpoint responses and return the cell to a homeostatic state following completion of DNA repair. These homeostatic functions may be partially responsible for the oncogenic effects of PPM1D when it is amplified and overexpressed in human tumors.
...
PMID:PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. 1587 Feb 57

Cells that encounter low nutrient conditions often respond by arresting cell division or becoming apoptotic. Recent work by Jones and colleagues (Jones et al.,2005) reveals how the AMP-activated kinase mediates this process by phosphorylating and activating the tumor suppressor p53.
...
PMID:AMPK and p53 help cells through lean times. 1586 71

The p53 tumor suppressor protein has a major role in protecting genome integrity. Under normal circumstances Mdmx and Mdm2 control the activity of p53. Both proteins inhibit the transcriptional regulation by p53, while Mdm2 also functions as an E3 ubiquitin ligase to target both p53 and Mdmx for proteasomal degradation. HAUSP counteracts the destabilizing effect of Mdm2 by direct deubiquitination of p53. Subsequently, HAUSP was shown to deubiquitinate Mdm2 and Mdmx, thereby stabilizing these proteins. The ATM protein kinase is a key regulator of the p53 pathway in response to double strand breaks (DSBs) in the DNA. ATM fine-tunes p53's response to DNA damage by directly phosphorylating it, by regulating additional post-translational modifications of this protein, and by affecting two p53 regulators: Mdm2 and Mdmx. ATM directly and indirectly induces Mdm2 and Mdmx phosphorylation, resulting in decreased activity and stability of these proteins. We recently provided a mechanism for the reduced stability of Mdm2 and Mdmx by showing that ATM-dependent phosphorylation lowers their affinity for the deubiquitinating enzyme HAUSP. Altogether, the emerging picture portrays an elaborate, but fine-tuned, ATM-mediated control of p53 activation and stabilization following DNA damage. Further insight into the mechanism by which ATM switches the interactions between HAUSP, Mdmx, Mdm2 and p53, to favor p53 activation may offer new tools for therapeutic intervention in the p53 pathway for cancer treatment.
...
PMID:ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation. 1608 21

The DNA damage checkpoint protein kinase mutated in ataxia telangiectasia (ATM) is involved in sensing and transducing DNA damage signals by phosphorylating and activating downstream target proteins that are implicated in the regulation of cell cycle progression and DNA repair. Atm-/- cells are defective in cellular proliferation mediated by the Arf/p53/p21 pathway. In this report, we show that increased expression of p21 (also known as Waf1 or CDKN1a) in Atm-/- cells serves as a cellular defense mechanism to suppress further chromosomal instability (CIN) and tumor development because Atm-/- p21-/- mice are predisposed to carcinomas and sarcomas with intratumoral heterogeneity. It was found that Atm-deficient cells are defective in metaphase-anaphase transition leading to abnormal karyokinesis. Moreover, Atm-/- p21-/- primary embryonic fibroblasts exhibit increased CIN compared with either Atm-/- or p21-/- cells. The increased CIN is manifested at the cellular level by increased chromatid breaks and elevated aneuploid genome in Atm-/- p21-/- cells. Finally, we showed that the role of p21 in a CIN background induced by loss of Atm is to suppress numerical CIN but not structural CIN. Our data suggest that the development of aneuploidy precedes tumor formation and implicates p21 as a major tumor suppressor in a genome instability background.
...
PMID:ATM and p21 cooperate to suppress aneuploidy and subsequent tumor development. 1620 44

Chromosomal translocations involving the immunoglobulin switch region are a hallmark feature of B-cell malignancies. However, little is known about the molecular mechanism by which primary B cells acquire or guard against these lesions. Here we find that translocations between c-myc and the IgH locus (Igh) are induced in primary B cells within hours of expression of the catalytically active form of activation-induced cytidine deaminase (AID), an enzyme that deaminates cytosine to produce uracil in DNA. Translocation also requires uracil DNA glycosylase (UNG), which removes uracil from DNA to create abasic sites that are then processed to double-strand breaks. The pathway that mediates aberrant joining of c-myc and Igh differs from intrachromosomal repair during immunoglobulin class switch recombination in that it does not require histone H2AX, p53 binding protein 1 (53BP1) or the non-homologous end-joining protein Ku80. In addition, translocations are inhibited by the tumour suppressors ATM, Nbs1, p19 (Arf) and p53, which is consistent with activation of DNA damage- and oncogenic stress-induced checkpoints during physiological class switching. Finally, we demonstrate that accumulation of AID-dependent, IgH-associated chromosomal lesions is not sufficient to enhance c-myc-Igh translocations. Our findings reveal a pathway for surveillance and protection against AID-dependent DNA damage, leading to chromosomal translocations.
...
PMID:Role of genomic instability and p53 in AID-induced c-myc-Igh translocations. 1640 Mar 28


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

---