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)

p73 is a novel member of the p53 family of tumor suppressor proteins which is involved in cellular differentiation, tumor suppression, and the response to genotoxic stress. The molecular mechanisms regulating p73 activity are still poorly understood. Recently, p73 was found to be a target of the enzymatic activity of c-Abl, a non-receptor tyrosine kinase that potently activated in response to DNA damage. Here, we present evidence that c-Abl induces the phosphorylation of p73 in threonine residues adjacent to prolines, and that the p38 MAP kinase pathway mediates this response. Furthermore, we found that activation of p38 is sufficient to enhance the stability of p73, and that the transcriptional activation of p73 by c-Abl requires the activity of p38. These findings indicate that members of the MAP kinases superfamily of signaling molecules can regulate p73, and support a role for the p38 MAP kinase in a novel biochemical pathway by which c-Abl regulates this p53-related molecule.
 ...
PMID:Regulation of p73 by c-Abl through the p38 MAP kinase pathway. 1184 Mar 43

p53 is an important player in the cellular response to genotoxic stress whose functions are regulated by phosphorylation of a number of serine and threonine residues. Phosphorylation of p53 influences its DNA-binding and gene regulation activities. This study examines p53 phosphorylation in HCT-116 (MMR-deficient) and HCT-116+ch3 (MMR-proficient) human colon cancer cells treated with a S(N)2 DNA-alkylating agent, methylmethane sulfonate (MMS). MMS induces phosphorylation of p53 on Ser15 and Ser392 in a dose- and time-dependent manner. MMS-induced p53 phosphorylation is independent of DNA mismatch repair (MMR) activity. Nuclear extracts from MMS-treated HCT-116 cells had higher p21WAF1/Cip1 (p21) promoter DNA-binding activity in vitro opposed to untreated cells. After MMS treatment, the activation of the cloned p21 promoter in a transient transfection assay and endogenous p21 mRNA levels in HCT-116(p53+/+) versus HCT-116(p53-/-) cells increased, which correlates with an increased levels of phospho-p53(Ser15) and phospho-p53(Ser392). These results suggest that SN2 DNA-alkylating agent-induced phosphorylation of p53 on Ser15 and Ser392 increases its DNA-binding properties to cause an increased expression of p21 that may play a role in cell cycle arrest and/or apoptosis of HCT-116 cells.
 ...
PMID:SN2 DNA-alkylating agent-induced phosphorylation of p53 and activation of p21 gene expression. 1189 Sep 31

We examined the mechanism of action of nitrosoureas as represented by 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) with respect to p53 and the G2M cell cycle checkpoint using two glioblastoma cell lines: U251MG and U373MG, with mutated p53. At log-phase cell growth, fresh medium containing ACNU (final concentration, 3, 10, or 30 microg/ml) was added. After 24 h of incubation, cells were harvested for flow cytometric or Western analysis. In both lines, cell numbers in the G0/G1 phase decreased with ACNU treatment. Cells accumulated in G2M and S phases, and the peak was shifted from G2M to the S phase in a concentration-dependent manner. In both cell lines, the amount of Cdc2 protein phosphorylated at the tyrosine 15 residue was increased 2- to 6-fold by treatment with ACNU compared with untreated control cells. Expression of cyclin B protein was suppressed in cells treated with 30 microg/ml ACNU. Protein abundance for total Cdc2, Cdc2 phosphorylated at the threonine 161 residue, Wee 1, Myt 1, Chk 1, and 14-3-3sigma was not affected by treatment with ACNU in either cell line. We suggest that a low concentration of ACNU should be used with adjuvant therapies that act upon cells in the G2M phase. A high concentration of ACNU should be used with adjuvant therapies that act upon cells in the S phase.
 ...
PMID:Suppression of Cdc2 dephosphorylation at the tyrosine 15 residue during nitrosourea-induced G2M phase arrest in glioblastoma cell lines. 1222 40

The Polo-like kinases (Plks) are a conserved family of kinases that contribute to cell cycle regulation, particularly in G2 and mitosis. In mammals, there are at least three members of the Plk family. Here we show that Plk3 is a stress response protein that becomes phosphorylated following DNA damage or mitotic spindle disruption. Phosphorylation enhances its kinase activity and is dependent upon ataxia telangiectasia-mutated (ATM) in the former case but not the latter. Plk3 associates with complexes of multiple sizes ranging from 150 to greater then 600 kDa. In its unphosphorylated form it elutes from a sizing column at about 400 kDa whereas it associates with complexes of 150 and 600 kDa when phosphorylated. Among the proteins with which it physically associates and utilizes, as substrates are Chk2 and P53. It phosphorylates Chk2 on a residue different from threonine 68 (Thr68), the principal target for ATM. While ATM is necessary for phosphorylation and activation of Chk2 in vivo, Plk3 seems to contribute to its full activation. In its phosphorylated form it also coelutes and forms a complex with unpolymerized tubulin. In aggregate, the data argue that Plk3 is a multifunctional protein that associates with multiple complexes and that contributes to response to stress incurred by DNA damage and mitotic spindle disruption, albeit via different pathways.
 ...
PMID:Mammalian Polo-like kinase 3 (Plk3) is a multifunctional protein involved in stress response pathways. 1224 61

Human exposure to arsenic, a ubiquitous and toxic environmental pollutant, is associated with an increased incidence of skin cancer. However, the mechanism(s) associated with AsIII-mediated toxicity and carcinogenesis at low levels of exposure remains elusive. Aberrations in cell proliferation, oxidative damage, and DNA-repair fidelity have been implicated in sodium arsenite (AsIII)-mediated carcinogenicity and toxicity, but these events have been examined in isolation in the majority of biological models of arsenic exposure. We hypothesized that the simultaneous interaction of these effects may be important in arsenic-mediated neoplasia in the skin. To evaluate this, normal human epidermal keratinocytes (NHEK) were exposed to nontoxic doses (0.005-5 micro M) of AsIII and monitored for several physiological endpoints at the times when cells were harvested for gene expression measurements (1-24 h). Two-fluor cDNA microarray analyses indicated that AsIII treatment decreased the expression of genes associated with DNA repair (e.g., p53 and Damage-specific DNA-binding protein 2) and increased the expression of genes indicative of the cellular response to oxidative stress (e.g., Superoxide dismutase 1, NAD(P)H quinone oxidoreductase, and Serine/threonine kinase 25). AsIII also modulated the expression of certain transcripts associated with increased cell proliferation (e.g., Cyclin G1, Protein kinase C delta), oncogenes, and genes associated with cellular transformation (e.g., Gro-1 and V-yes). These observations correlated with measurements of cell proliferation and mitotic measurements as AsIII treatment resulted in a dose-dependent increase in cellular mitoses at 24 h and an increase in cell proliferation at 48 h of exposure. Data in this manuscript demonstrates that AsIII exposure simultaneously modulates DNA repair, cell proliferation, and redox-related gene expression in nontransformed, normal NHEK. It is anticipated that data in this report will serve as a foundation for furthering our knowledge of AsIII-regulated gene expression in skin and other tissues and contribute to a better understanding of arsenic toxicity and carcinogenesis.
 ...
PMID:Coordination of altered DNA repair and damage pathways in arsenite-exposed keratinocytes. 1237 79

DNA damage leads to stabilization and accumulation of p53, which plays a pivotal role in transcriptional activation of p21 and cell cycle arrest. The increase in p53 stability depends critically on its phosphorylation on serine/threonine residues, including those preceding a proline (Ser(P)/Thr-Pro). The Ser(P)/Thr-Pro moiety exists in the two distinct cis and trans conformations and their conversion is catalyzed specifically by the prolyl isomerase Pin1. Pin1 regulates the conformation and function of certain phosphorylated proteins and plays an important role in cell cycle regulation, oncogenesis, and Alzheimer's disease. However, nothing is known about the role of Pin1 in DNA damage. Here we found that DNA damage enhanced the interaction between Pin1 and p53, which depended on the WW domain in Pin1 and Ser(33/46)-Pro motifs in p53. Furthermore, Pin1 regulates the stability of p53 and its transcriptional activity toward the p21 promoter. As a result, p53 and p21 barely increased after DNA damage in Pin1 knock-out embryonic fibroblasts or in neoplastic cells depleted of Pin1. Moreover, Pin1 null cells displayed significant defects in cell cycle checkpoints induced by DNA damage. These results demonstrate a new role of Pin1 in regulating p53 function during DNA damage.
 ...
PMID:Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage. 1238 58

Possible inhibitory effects of hepatitis C virus (HCV) proteins on cellular protein synthesis were analyzed using transient expression system. The core protein, the nonstructural protein 4A (NS4A) and NS4B, but not NS3, NS5A or NS5B, inhibited p21/Waf1 expression post-transcriptionally. Further analysis revealed that the inhibition by NS4A and NS4B was mediated at least partly, if not entirely, at the translation level. NS4A-mediated translational inhibition was counteracted to some extent by NS3 co-expressed either in trans or cis. Co-expression of NS4A and NS4B exerted an additive effect on the translational inhibition. The N-terminal two-thirds of NS4A (amino acids 1-40) was shown to be involved in the translational inhibition. We also tested possible inhibitory effects of NS4A and NS4B on synthesis of other cellular proteins in parallel with p21/Waf1. NS4A and NS4B inhibited p21/Waf1 most strongly, followed by RNase L, p53, a C-terminally truncated form of CREB-RP and 2'-5' oligoadenylate synthetase. p21/Waf1, RNase L and p53 are known to have the PEST (proline-glutamic acid-serine-threonine) motif with relatively high scores in their sequences and considered to be sensitive to intracellular degradation. Taken together, our results suggest that NS4A and NS4B each mediate translational inhibition and, probably, increased degradation of certain cellular proteins.
 ...
PMID:Inhibition of protein synthesis by the nonstructural proteins NS4A and NS4B of hepatitis C virus. 1245 68

Serine/threonine phosphatase 5 (PP5) can act as a suppresser of p53-dependent growth suppression and has been reported to associate with several proteins, including the glucocorticoid receptor/heat-shock protein-90 complex. Still, the physiological/pathological roles of PP5 are unclear. To characterize the relationship of PP5, glucocorticoid receptor activation and p53, here we describe the development of chimeric antisense oligonucleotides that potently inhibit human p53 expression. This allowed us to regulate the expression of either p53 (e.g. with ISIS 110332) or PP5 (e.g. with ISIS 15534) in genetically identical cells. Studies with ISIS 110332 revealed that the suppression of p53 expression is associated with a decrease in the basal expression of the cyclin-dependent kinase inhibitor protein, p21(WAF1/Cip1), and a concomitant increase in the rate of cell proliferation. Suppression of p53 also blocks dexamethasone-induced p21(WAF1/Cip1) expression and G(1)-growth arrest. Furthermore, treatment with ISIS 110332, but not the mismatched controls, ablates the suppression of growth produced by prior treatment with dexamethasone. Additional studies revealed that dexamethasone-dependent p21(WAF1/Cip1) expression occurs without an apparent change in p53 protein levels or the phosphorylation status of p53 at Ser-6, -37, or -392. However, dexamethasone treatment is associated with an increase in p53 phosphorylation at Ser-15. Suppression of PP5 expression with ISIS 15534 also results in the hyperphosphorylation of p53 at Ser-15. Together, these findings indicate that the basal expression of p53 plays a functional role in a glucocorticoid receptor-mediated response regulating the expression of p21(Waf1/Cip1) via a mechanism that is suppressed by PP5 and associated with the phosphorylation of p53 at Ser-15.
 ...
PMID:Identification of a functional link for the p53 tumor suppressor protein in dexamethasone-induced growth suppression. 1251 80

Phosphorylation of proteins on serine or threonine residues preceding proline (Ser/Thr-Pro) is a major intracellular signaling mechanism. The phosphorylated Ser/Thr-Pro motifs in a certain subset of phosphoproteins are isomerized specifically by the peptidyl-prolyl cis-trans isomerase Pin1. This post-phosphorylation isomerization can lead to conformational changes in the substrate proteins and modulate their functions. Pin1 interacts with a number of mitotic phosphoproteins, and plays a critical role in mitotic regulation. Recent work indicates that Pin1 is overexpressed in many human cancers and plays an important role in oncogenesis. Pin1 regulates the expression of cyclin D1 by cooperating with Ras signaling and inhibiting the interaction of beta-catenin with the tumor suppressor APC and also directly stabilizing cyclin D1 protein. Furthermore, PIN1 is an E2F target gene essential for the Neu/Ras-induced transformation of mammary epithelial cells. Pin1 is also a critical regulator of the tumor suppressor p53 during DNA damage response. Given its role in cell growth control and oncogenesis, Pin1 could represent a new anti-cancer target.
 ...
PMID:Prolyl isomerase Pin1: a catalyst for oncogenesis and a potential therapeutic target in cancer. 1257 Dec 75

Forkhead-homology-associated (FHA) domains function as protein-protein modules that recognize phosphorylated serine/threonine motifs. Interactions between FHA domains and phosphorylated proteins are thought to have essential roles in the transduction of DNA damage signals; however, it is unclear how FHA-domain-containing proteins participate in mammalian DNA damage responses. Here we report that a FHA-domain-containing protein-mediator of DNA damage checkpoint protein 1 (MDC1; previously known as KIAA0170)--is involved in DNA damage responses. MDC1 localizes to sites of DNA breaks and associates with CHK2 after DNA damage. This association is mediated by the MDC1 FHA domain and the phosphorylated Thr 68 of CHK2. Furthermore, MDC1 is phosphorylated in an ATM/CHK2-dependent manner after DNA damage, suggesting that MDC1 may function in the ATM-CHK2 pathway. Consistent with this hypothesis, suppression of MDC1 expression results in defective S-phase checkpoint and reduced apoptosis in response to DNA damage, which can be restored by the expression of wild-type MDC1 but not MDC1 with a deleted FHA domain. Suppression of MDC1 expression results in decreased p53 stabilization in response to DNA damage. These results suggest that MDC1 is recruited through its FHA domain to the activated CHK2, and has a critical role in CHK2-mediated DNA damage responses.
 ...
PMID:MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways. 1260 4


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