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

We tested the hypothesis that individual variations in the induction of the TP53 tumor suppressor protein by radiation are related to inherent radiosensitivity. Thirty-two fibroblast cell strains were examined. Radiosensitivity was measured by a clonogenic survival assay. The induction of TP53 and its transcriptionally activated CDKN1A (p21) protein were studied by Western blotting 3 h after a single dose of 5 Gy. The relative cell culture age, as determined by the colony size distribution, was studied as a confounding factor. Survival curves showed wide range of radiosensitivity. The surviving fraction at 2 Gy (SF2) ranged between 0.02 and 0.49 (mean = 0.29, SD = 0.13). TP53 induction ranged between 1.28 and 2.34 (mean = 1.80, SD = 0.31). CDKN1A showed a wider induction (1.09-4.05, mean = 2.33, SD = 0.78). Positive correlations were observed between SF2 and TP53 induction (R(2) = 0.62, P < 0.001) and CDKN1A (R(2) = 0.64, P < 0.001). No correlation with the colony size distribution was observed. In conclusion, these results suggest that the individual variations in radiosensitivity and in the level of induction of TP53 (and consequently CDKN1A) are congruent, irrespective of the genetic background of these nontransformed fibroblasts. It is postulated that underlying mechanisms culminating in a stronger TP53 induction lead to higher survival, presumably due to more efficient repair of radiation-induced damage.
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PMID:Evidence that individual variations in TP53 and CDKN1A protein responsiveness are related to inherent radiation sensitivity. 1721 16

p21(WAF1/CIP1), transcribed from the CDKN1A locus, plays a key role executing p53-induced growth arrest. The recent discovery that an alternative transcript, p21B, induces apoptosis, suggests an additional important function of this gene. Here, we report p21 and p21B mutation status in large cohorts of breast cancers and compare distributions of p21B polymorphisms in cancer patients to healthy controls. In 521 breast tumor samples analyzed, only one point mutation affecting the p21B protein was observed. No mutations were found when screening a panel of 20 established cell lines. A novel polymorphism, p21B(G128T) was identified. Haplotype analysis revealed no association between this variant and the previously identified p21B polymorphism p21B(T35C) or any of the known p21(WAF1/CIP1) polymorphisms. As previously reported for p21B(T35C), distribution of p21B(G128T) was similar among breast cancer patients and healthy controls (n = 691 and 1,015; incidence 6.1 vs. 4.8%; p = 0.273, respectively). No association between p21B(G128T) or p21B(T35C) and response to chemotherapy with an anthracycline-containing regimen or paclitaxel was recorded. Our findings do not suggest mutations or polymorphisms of p21B to play a major role with respect to either breast cancer risk or sensitivity towards chemotherapy.
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PMID:Mutations and polymorphisms of the p21B transcript in breast cancer. 1744 96

Inherent radiosensitivity varies widely between individuals. We hypothesized that amino acid substitution variants in two highly radiation-responsive proteins, TP53 (p53) and CDKN1A (p21, Waf1, Cip1), are associated with and could explain individual variations in radiosensitivity. The two non-synonymous single-nucleotide polymorphisms (SNPs) TP53 codon 72 Arg/Pro G>C and CDKN1A codon 31 Ser/Arg C>A were genotyped in 92 normal fibroblast cell strains of different radiosensitivity. The clonogenic surviving fraction at 2 Gy (SF2) ranged between 0.15 and 0.50 (mean = 0.34, SD = 0.08). The mean SF2 was used to divide the cell strains into radiosensitive (45) and normal groups (47). A significant association was observed between SF2 and the TP53 codon 72 haplotype (C compared to G, P = 0.01). No association was observed between CDKN1A codon 31 haplotype and radiosensitivity (P = 0.86). The variant TP53 Arg72 allele was associated with a decrease in radiosensitivity, presumably due to suboptimal function leading to less stringent control of cell division. We conclude that certain SNPs in susceptible genes can influence cellular radiation response. Such risk alleles could ultimately be used as predictive markers for radiosensitivity to help stratifying individuals during assessment of risk of radiation exposure.
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PMID:Association between TP53 codon 72 single-nucleotide polymorphism and radiation sensitivity of human fibroblasts. 1747 97

Damage-induced G1 checkpoint in mammalian cells involves upregulation of p53, which activates transcription of p21(Waf1) (CDKN1A). Inhibition of cyclin-dependent kinase (CDK)2 and CDK4/6 by p21 leads to dephosphorylation and activation of Rb. We now show that ectopic p21 expression in human HT1080 fibrosarcoma cells causes not only dephosphorylation but also depletion of Rb; this effect was p53-independent and susceptible to a proteasome inhibitor. CDK inhibitor p27 (CDKN1B) also caused Rb dephosphorylation and depletion, but another CDK inhibitor p16 (CDKN2A) induced only dephosphorylation but not depletion of Rb. Rb depletion was observed in both HT1080 and HCT116 colon carcinoma cells, where p21 was induced by DNA-damaging agents. Rb depletion after DNA damage did not occur in the absence of p21, and it was reduced when p21 induction was inhibited by p21-targeting short hairpin RNA or by a transdominant inhibitor of p53. These results indicate that p21 both activates Rb through dephosphorylation and inactivates it through degradation, suggesting negative feedback regulation of damage-induced cell-cycle checkpoint arrest.
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PMID:p21(Waf1/Cip1/Sdi1) mediates retinoblastoma protein degradation. 1748 59

We seek to determine whether cellular radiosensitivity in nineteen human colorectal tumor cell lines and three human glioblastoma tumor cell lines segregate into statistically distinct groups and whether such groups correlate with gene expression. We measure clonogenic survival in 22 cell lines that vary in radiosensitivity and in expression of selected genes: ATM, TP53, CDKN1A, 14-3-3sigma, Ki-ras and DNA mismatch repair genes. We describe and compare radiosensitivity in these cell lines by one-parameter or two parameter analysis. Radiosensitivity varies among and between colorectal tumor cell lines and glioblastoma cell lines. When compared directly using survival, or using two-parameter analysis of radiosensitivity, cell lines distribute into four statistically-significant radiosensitivity groups. These groups associate strongly with the status of two genes, ATM and TP53, but do not associate with CDKN1A, 14-3-3sigma, Ki-ras and DNA mismatch repair genes. Intrinsic cellular radiosensitivity of 22 colorectal and glioblastoma cell lines fall into four radiosensitivity groups that associate with expression of ATM and TP53. These analyses suggest multiple mechanisms underlay intrinsic cellular radiosensitivity.
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PMID:Human tumor cells segregate into radiosensitivity groups that associate with ATM and TP53 status. 1756 39

Cell cycle arrest in response to DNA damage involves protein stabilization and consequent upregulation of p53, which induces transcription of cyclin-dependent kinase inhibitor p21 (CDKN1A). We now show that p21 acts as a negative regulator of the cellular levels of p53. p21 knockdown by short hairpin RNA strongly increased p53 upregulation by a DNA-damaging drug doxorubicin in HT1080 fibrosarcoma cells. A protease inhibitor N-Ac-Leu-Leu-norleucinal (ALLN) drastically increased the amount of p53 in HCT116 colon carcinoma cells, but it had no effect on the already high p53 level in a p21(-/-) derivative of this cell line. Inhibition of transcription, which increases p53 levels in different cell lines due to the degradation of p53-destabilizing proteins such as Mdm2, failed to increase but instead decreased the amount of p53 in p21(-/-) cells, despite a drastic decrease in the level of Mdm2. These results indicate that p21 acts as a negative regulator of p53 stability in different cell types. p53 regulation by p21 may provide a negative regulatory loop that limits p53 induction.
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PMID:p21 (CDKN1A) is a negative regulator of p53 stability. 1758 1

The nephrotoxic potential of the widely used immunosuppressive agent cyclosporine A (CsA) is well recognized. However, the mechanism of renal tubular toxicity is not yet fully elucidated. Chronic CsA nephropathy and renal organ aging share some clinical features, such as renal fibrosis and tubular atrophy, raising the possibility that CsA may exert some of its deleterious effects via induction of a stress-induced senescent phenotype. We investigated this hypothesis in HK-2 cells and primary proximal tubular cells in vitro. CsA induced the production of H2O2, caused cell cycle arrest in the G0/G1 phase, and inhibited DNA synthesis. Furthermore, CsA exposure lead to a reduction of telomere length, increased p53 serine 15 phosphorylation, and caused an upregulation of the cell cycle inhibitor p21(Kip1) (CDKN1A) mRNA levels. CsA caused an increase in p16(INK4a) (CDKN2A) expression after a 13-day exposure in primary proximal tubular cells but not in HK-2 cells. Coincubation of cells with CsA and catalase was able to prevent telomere shortening and partially restored DNA synthesis. In summary, CsA induces cellular senescence in human renal tubular epithelial cells, which can be attenuated by scavenging reactive oxygen species.
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PMID:Cyclosporine A induces senescence in renal tubular epithelial cells. 1759 34

Defects in DNA damage responses may underlie genetic instability and malignant progression in melanoma. Cultures of normal human melanocytes (NHMs) and melanoma lines were analyzed to determine whether global patterns of gene expression could predict the efficacy of DNA damage cell cycle checkpoints that arrest growth and suppress genetic instability. NHMs displayed effective G1 and G2 checkpoint responses to ionizing radiation-induced DNA damage. A majority of melanoma cell lines (11/16) displayed significant quantitative defects in one or both checkpoints. Melanomas with B-RAF mutations as a class displayed a significant defect in DNA damage G2 checkpoint function. In contrast the epithelial-like subtype of melanomas with wild-type N-RAS and B-RAF alleles displayed an effective G2 checkpoint but a significant defect in G1 checkpoint function. RNA expression profiling revealed that melanoma lines with defects in the DNA damage G1 checkpoint displayed reduced expression of p53 transcriptional targets, such as CDKN1A and DDB2, and enhanced expression of proliferation-associated genes, such as CDC7 and GEMININ. A Bayesian analysis tool was more accurate than significance analysis of microarrays for predicting checkpoint function using a leave-one-out method. The results suggest that defects in DNA damage checkpoints may be recognized in melanomas through analysis of gene expression.
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PMID:Defective cell cycle checkpoint functions in melanoma are associated with altered patterns of gene expression. 1759 16

Despite the potential importance of the cell cycle and apoptosis pathways in brain tumor etiology, little has been published regarding brain tumor risk associated with common gene variants in these pathways. Using data from a hospital-based case-control study conducted by the National Cancer Institute between 1994 and 1998, we evaluated risk of glioma (n = 388), meningioma (n = 162), and acoustic neuroma (n = 73) with respect to 12 single nucleotide polymorphisms from 10 genes involved in apoptosis and cell cycle control: CASP8, CCND1, CCNH, CDKN1A, CDKN2A, CHEK1, CHEK2, MDM2, PTEN, and TP53. We observed significantly decreased risk of meningioma with the CASP8 Ex14-271A>T variant [odds ratio (OR)(AT), 0.8; 95% confidence interval (95% CI), 0.5-1.2; OR(AA), 0.5; 95% CI, 0.3-0.9; P(trend) = 0.03] and increased risk of meningioma with the CASP8 Ex13+51G>C variant (OR(GC), 1.4; 95% CI, 0.9-2.1; OR(CC), 3.6; 95% CI, 1.0-13.1; P(trend) = 0.04). The CT haplotype of the two CASP8 polymorphisms was associated with significantly increased risk of meningioma (OR, 1.7; 95% CI, 1.1-2.6), but was not associated with risk of glioma or acoustic neuroma. The CCND1 Ex4-1G>A variant was associated with increased risk for glioma, and the Ex8+49T>C variant of CCNH was associated with increased risk of glioma and acoustic neuroma. The MDM2 Ex12+162A>G variant was associated with significantly reduced risk of glioma. Our results suggest that common variants in the CASP8, CCND1, CCNH, and MDM2 genes may influence brain tumor risk. Future research in this area should include more detailed coverage of genes in the apoptosis/cell cycle control pathways.
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PMID:Polymorphisms in apoptosis and cell cycle control genes and risk of brain tumors in adults. 1768 42

Germ line mutations of the p53 gene are known to cause Li-Fraumeni syndrome, and a germ line p53 mutation has recently been reported in a small subset of familial gastric cancer (FGC) in Europe and Korea. Although the incidence of gastric cancer is very high in Japan and familial clustering is not uncommon, there has been little information on the genetic factors of FGC. Therefore, to determine the role of germ line p53 mutations in FGC in the Japanese population in this study, we used sequencing analysis to examine 80 individuals from 35 Japanese FGC families without germ line CDH1 mutations for germ line p53 mutations. One missense (c.91G>A: p.Val31Ile) and two intronic germ line mutations were found, and transcriptional activity of the Ile31 mutant on p53-responsive genes was examined to determine the functional effect of the novel p.Val31Ile germ line mutation. A luciferase reporter assay showed that the transcriptional activity of p21 (CDKN1A) and MDM2 promoters but not of the BAX promoter was significantly lower in the Ile31-type p53 than in the wild-type (wt) p53. Next, doxycycline-regulated p53-inducible H1299 cell lines were established by applying a retrovirus-mediated gene transfer system to a p53-null human H1299 cell line. Under similar p53 expression conditions shown by western blot and immunofluorescence analyses, a cell proliferation assay showed that the Ile31-type p53 had significantly lower cell proliferation suppressing activity than wt p53. These results suggest that Ile31-type p53 may be partly involved in FGC because of its low transcriptional activity and low cell proliferation suppressing activity.
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PMID:Identification and characterization of a novel germ line p53 mutation in familial gastric cancer in the Japanese population. 1769 Jan 13


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