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)

The cyclin-dependent kinase inhibitor 2a (Cdkn2a) locus encodes two distinct tumor suppressors, p16INK4a and p19ARF, whose functions interrelate in the regulation of cell proliferation as key components of the retinoblastoma and p53 pathways, respectively. In many types of cancer, alterations of Cdkn2a abrogate the functions of both suppressors, implying that both are integral to the genesis of certain cancer types. While this has been observed in mouse lung adenocarcinogenesis, recent observations also suggested that naturally occurring variation at the Cdkn2a locus is probably operative in the development of these tumors. Firstly, two common haplotypes of mouse Cdkn2a have been identified, each of which encodes cosegregating variants of p16INK4a and p19ARF. The p16INK4a variants differ at amino acids 18 (histidine or proline) and 51 (valine or isoleucine), whereas the p19ARF variants differ only at amino acid 72 (histidine or arginine). Secondly, genetic resistance to lung tumor formation appears to segregate with one particular haplotype, which also is deleted preferentially in lung adenocarcinomas of Cdkn2a heterozygous mice. Here we attempt to explain these observations and to characterize further the roles of p16INK4 and p19ARF in mouse lung tumorigenesis by examining the function and expression of each of the variants of Cdkn2a. Functional analysis showed that the proline 18/isoleucine 51 p16INK4a variant was diminished in cdk6 binding, cdk6 inhibition and NIH/3T3 fibroblast growth suppression compared with the histidine 18/valine 51 variant, whereas both of the p19ARF variants suppressed growth with similar potencies. Also, the different alleles for p16INK4a and p19ARF were transcribed equally in the normal lungs of Cdkn2a heterozygotes, as determined by comparative reverse transcription-polymerase chain reaction-single-stranded conformation polymorphism analysis. These results indicate that strain-specific variation in p16INK4a function is exploited in mouse lung tumorigenesis and strongly implicate a role for p16INK4a in lung cancer predisposition and development.
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PMID:Cdkn2a encodes functional variation of p16INK4a but not p19ARF, which confers selection in mouse lung tumorigenesis. 1036 10

Suicide gene therapy systems such as the herpes simplex thymidine kinase/ganciclovir system (TK/GCV) may kill cancer cells by apoptosis through as yet undefined mechanisms. Here we show that TK/GCV treatment induces p53 accumulation and increases cell surface expression of CD95 and tumor necrosis factor receptor, which is likely to involve p53-mediated translocation of CD95 to the cell surface. TK/GCV-induced apoptosis involves CD95-L-independent CD95 aggregation leading to the formation of a Fas-associated death domain protein (FADD) and caspase-8-containing, death-inducing signaling complex. Dominant negative FADD, the caspase-8 inhibitor zIETD-fmk [Z-Ile-Glu(OMe)-Thr-Asp(OMe)-fluoromethylketone], and zVAD-fmk (Z-Val-Ala-Asp-fluoromethylketone) partially abrogate TK/GCV-induced apoptosis. In addition to apoptosis induction, TK/GCV treatment strongly sensitizes for CD95-L-, TNF-, and TNF-related, apoptosis-inducing, ligand (TRAIL)-induced cell death in constitutively resistant cells. These findings may be used to increase the efficacy of TK/GCV and other suicide gene therapy systems for the treatment of cancer.
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PMID:Herpes simplex virus thymidine kinase/ganciclovir-induced apoptosis involves ligand-independent death receptor aggregation and activation of caspases. 1041 38

Li-Fraumeni syndrome is an autosomal dominant disorder that is characterized by various types of cancer in childhood and adult cases. Although hereditary TP53 mutation is very rare in different human cancers, it has been frequently reported in Li-Fraumeni syndrome. On the other hand, hereditary mutations of TP57KIP2, P15INK4B, and P16INK4A, which affect the cell cycle similar to TP53, were observed in some types of cancer. In a Turkish family with the diagnosis of Li-Fraumeni syndrome, we analyzed the mutation pattern of TP53, P57KIP2, P15INK4B, and P16INK4A in the peripheral blood, and loss of heterozygosity (homo/hemizygous deletion) pattern of TP53 and P15INK4B/P16INK4A in two tumor tissues. The propositus had a seminoma, his daughter a medulloblastoma, and one of his healthy cousins, a TP53 codon 292 missense point mutation (AAA-->ATA; Lys-->Ile) in the peripheral blood cells. Tumor tissue obtained from the propositus with the seminoma revealed loss of heterozygosity in the TP53 gene. In the analyses of tumor tissues from the propositus and his daughter, a P16INK4A codon 94 missense point mutation (GCG-->GAG; Ala-->Glu) was observed with the hereditary TP53 mutation. P16INK4A codon 94 mutation observed in our family is a novel mutation in Li-Fraumeni syndrome. No other gene alteration in TP53, P57KIP2, P15INK4B, and P16INK4A was observed. Existence of the P16INK4A mutation and the hereditary TP53 mutation with or without loss of heterozygosity in the TP53 gene (seminoma/medulloblastoma) may be evidence for a common mechanism involved in tumorogenesis. The gene alterations in TP53 and P16INK4A genes may be used as tumor markers in our family.
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PMID:Hereditary TP53 codon 292 and somatic P16INK4A codon 94 mutations in a Li-Fraumeni syndrome family. 1572 47

The hormonally active form of vitamin D3, 1,25-dihydroxyvitamin D3, and its two analogues, EB 1089 and CB 1093, are novel putative anticancer agents with an interesting profile of induction of growth inhibition, differentiation, and apoptosis in tumor cells. To study the signaling pathways mediating these events, we used two human breast cancer cell lines: MCF-7 cells, expressing a wild-type p53 tumor suppressor protein, and T47D cells, lacking a functional p53. Vitamin D compounds induced a growth arrest followed by apoptosis in both cell lines at concentrations ranging from 1 to 100 nM, indicating that p53 is not necessary for growth-inhibitory effects induced by vitamin D compounds. Surprisingly, apoptosis induced by these compounds occurred also independently of known caspases. Inhibition of caspase activation by overexpression of a cowpox-derived caspase inhibitor CrmA or by addition of inhibitory peptides acetyl-Asp-Glu-Val-Asp-aldehyde (200 microM), acetyl-Ile-Glu-Thr-Asp-aldehyde (50 microM), and Z-Val-Ala-D,L-Asp-fluoromethylketone (1 microM) showed no effect on the induction of growth arrest or apoptosis by vitamin D compounds under assay conditions in which apoptosis induced by TNF or staurosporine was effectively inhibited. Moreover, overexpression of caspase-3 in MCF-7 cells had no sensitizing effect to vitamin D compounds, and neither caspase-3-like protease activity nor cleavage of a caspase substrate poly(ADP)ribose polymerase was detected in lysates from apoptotic cells following the treatment with these compounds. Contrary to CrmA, overexpression of an antiapoptotic protein Bcl-2 in MCF-7 cells conferred a nearly complete protection from apoptosis induced by vitamin D compounds. Taken together, these data indicate that vitamin D compounds induce apoptosis via a novel caspase- and p53-independent pathway that can be inhibited by Bcl-2. This may prove useful in the treatment of tumors that are resistant to therapeutic agents that are dependent on the activation of p53 and/or caspases.
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PMID:Apoptosis induced by vitamin D compounds in breast cancer cells is inhibited by Bcl-2 but does not involve known caspases or p53. 1051 95

The cerebellar medulloblastoma (WHO Grade IV) is a highly malignant, invasive embryonal tumor with preferential manifestation in children. Several molecular alterations appear to be involved, including isochromosome 17q and the p53, PTCH, and beta-catenin gene mutations. In this study, 46 sporadic medulloblastomas were screened for the presence of mutations in genes of the Wnt signaling pathway (APC and beta-catenin). Single-strand conformational polymorphism (SSCP) analysis followed by direct DNA sequencing revealed 3 miscoding APC mutations in 2 (4.3%) medulloblastomas. One case contained a GCA-->GTA mutation at codon 1296 (Ala-->Val), and another case had double point mutations at codons 1472 (GTA-->ATA, Val-->Ile) and 1495 (AGT-->GGT, Ser-->Gly). Miscoding beta-catenin mutations were detected in 4 tumors (8.7%). Three of these were located at codon 33 (TCT -->TTT, Ser-->Phe) and another at codon 37 (TCT-->GCT, Ser-->Ala). Adenomatous polyposis coli (APC) gene and beta-catenin mutations were mutually exclusive and occurred in a total of 6 of 46 cases (13%). Although germline APC mutations are a well established cause of familial colon and brain tumors (Turcot syndrome), this study provides the first evidence that APC mutations are also operative in a subset of sporadic medulloblastomas.
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PMID:APC mutations in sporadic medulloblastomas. 1066 72

The dietary isothiocyanates and cancer chemopreventive agents phenethyl isothiocyanate and allyl isothiocyanate and their cysteine conjugates inhibited the growth and induced apoptosis of human leukaemia HL60 (p53-) and human myeloblastic leukaemia-1 cells (p53+) in vitro. The median growth inhibitory concentration (GC(50)) values were in the range 1.49-3.22 microM in cultures with 10% serum. Isothiocyanates and cysteine conjugates had increased potency against HL60 cells in serum-free medium, with GC(50) values of 0.8-0. 9 microM. The potency of the compounds decreased with increased serum content of the medium, but that of the cysteine conjugates decreased more markedly. Growth inhibition and toxicity was characterised by either a rapid interaction of the isothiocyanate with the cells in the first hour of culture or exposure to isothiocyanate liberated from the cysteine conjugate in the initial 3 hr of culture, inhibition of macromolecule synthesis, and a commitment to apoptosis which developed in the initial 24 hr. Activities of caspase-3 and caspase-8 were increased during isothiocyanate-induced apoptosis, but caspase-1 activity was not. The general caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone and the specific caspase-8 inhibitor N-benzyloxycarbonyl-Ile-Glu(OMe)-Thr-Asp(OMe)-fluoromethylketone inhibited apoptosis, but specific caspase-1 and caspase-3 inhibitors did not. The antiproliferative activities were limited by hydrolysis of the isothiocyanate. This suggests that caspase-8 has a critical role, and caspase-3 a supporting role, in isothiocyanate-induced apoptosis in which p53 is not an obligatory participant. Isothiocyanate-induced apoptosis may suppress the growth of preclinical tumours and contribute to the well-established decreased cancer incidence associated with a vegetable-rich diet.
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PMID:Studies on the mechanism of the inhibition of human leukaemia cell growth by dietary isothiocyanates and their cysteine adducts in vitro. 1082 67

We have analyzed the expression of the CDKN1A (p21(CIP1)), CDKN1B (p27(Kip1)), TP53, RB1 and MDM2 proteins and tumor cell proliferation by immunohistochemical staining in 59 cases of metastatic melanoma. The genomic status of the CDKN2A (INK4-ARF, p16/p14(ARF)), CDKN2B (p15) and CDKN2C (p18) genes was determined by PCR-SSCP (single-strand conformation polymorphism) in 46 of these cases. These results were correlated with various clinico-pathological parameters, including the outcome of combined chemoimmunotherapy. We found positive correlations between the expression of CDKN1A and MDM2 (r = 0.5063, P = 0.001), between the expression of CDKN1B and RB1 (r = 0.5026, P = 0.001), and between RB1 expression and tumor cell proliferation (0.5564, P<0.001). Two mutations in the CDKN2A (p16) gene were detected, including a novel base change AAC-->ATC (Asn to Ile) at codon 71, that also changes the codon 85 of the alternative reading frame gene p14(ARF) from CAA to CAT (Gln to His). Homozygous deletion at exon 2 of the CDKN2A (INK4-ARF) gene was detected in six cases. In seven cases, the 540C-->G polymorphism in the 3'UTR of the CDKN2A (p16) gene was found in linkage disequilibrium with the 74C-->A polymorphism in intron 1 of the CDKN2B gene (P < 0.0001). These cases had significantly lower expression of the TP53 protein (P = 0.0032). Both 540C-->G and 580C-->T polymorphisms in the 3'UTR of the CDKN2A (p16) gene were associated with significantly shorter progression time from primary to metastatic disease (P = 0.0071). We conclude, that although none of the analyzed cell cycle regulators could be singled out as a major prognostic factor, G(1)/S checkpoint abnormalities remain one of the most significant factors in the development of malignant melanoma.
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PMID:Analysis of G(1)/S checkpoint regulators in metastatic melanoma. 1086 49

Somatic mutations in the p53 tumor suppressor gene are the most common genetic alterations found in human malignancies. In the present study, we studied 36 primary human breast carcinomas, using a polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and sequencing analysis of exons 2 through 9 for the presence of p53 gene mutations. Six of 36 (17%) breast cancers contained mutations within the core domain of the p53 protein responsible for sequence-specific DNA binding (codons 102-292); all 5 missense mutations clustered between codons 240 and 291 (codons 240, 243, 250, 285, and 291), whereas one nonsense mutation occurred at codon 199. By using recombinant PCR in vitro mutagenesis, we introduced point mutations at codons 199 from Gly to stop (gly199stop), 240 from Ser to Ile (ser240Ile), 250 from Pro to Ala (pro250ala), 285 from Glu to Lys (glu285lys), and 291 from Lys to Asn (lys291asn), and all the p53 sequences were subcloned into the CMVneoBam vector under the control of the cytomegalovirus (CMV) promoter. To test whether the mutants p53 were functionally wild-type (wt) or mutant, we transfected them to p53-null Saos-2 cells with a reporter plasmid containing a p53-responsive element, and performed chloramphenicol acetyltransferase (CAT) assay. Transient CAT assay for transcriptional activation revealed that one group, including gly199stop, ser240ile, glu285lys, and lys291asn, abolished the transcriptional activity, whereas the other group, including pro250ala, retained stronger transcriptional transactivation activity than that of wt p53.
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PMID:Identification of p53 gene mutations in breast cancers and their effects on transcriptional activation function. 1090 Nov 65

The p53 tumor suppressor protein functions as a transcription factor. It has, however, been previously reported that some p53 mutants are able to suppress cell growth independent of their transcriptional activity [Kaneuchi et al., (1999)]. In order to investigate the correlations between the trans-activation and growth-suppressive functions of p53, we have analyzed five p53 mutants by CAT reporter assay, colony formation assay, and growth-rate analysis. Five p53 mutants [Oh et al., (2000)]--199stop (Gly-->stop), 240ile (Ser-->Ile), 250ala (Pro-->Ala), 285lys (Glu-->Lys), and 291asn (Lys-->Asn)--were cotransfected with a reporter construct containing a p53-responsive element and then tested for their trans-activational activity in p53-null Saos-2 cells. As a result of a change in the protein structure, trans-activational activity was negated in 199stop, 240ile, 285lys, and 291asn, while 250ala retained its activity. Colony formation assay revealed that mutants 240ile and 250ala retained their growth suppression, while 199stop, 285lys, and 291asn did not. To study the features of these proteins, a group of isogenic cell lines that express mutant forms of p53 was generated from HeLa cells, and their growth rate was then examined: one group, containing 199stop, 285lys, and 291asn, showed a rapid growth rate, similar to that of the original HeLa cells; the other group, containing 240ile and 250ala, however, exhibited a slow growth rate. In conclusion, mutant p53 240ile, which completely lost its trans-activational activity, nevertheless continued to exhibit its growth-suppressive activity. Further work is required to understand how 240ile is involved in growth suppression.
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PMID:The p53 mutation which abrogates trans-activation while maintaining its growth-suppression activity. 1098 34

The interaction of genetic and environmental factors can determine an individual's susceptibility to various cancers. We present a hospital-based case-control study, which included 90 patients of esophageal squamous-cell carcinoma (ESCC) and 254 healthy people in Taiwan, to investigate the effects of genetic polymorphisms of p53, GSTP1 and NAT2 on the risk of ESCC. Polymorphisms of p53, NAT2 and GSTP1 were determined by PCR-RFLP. The codon 72 p53 Pro allele was more frequently found in ESCC patients [odds ratio (OR) 1.86, 95% confidence interval (CI) 1.04-3.35 for Arg/Pro genotype and OR 2.56, 95% CI 1.29-5.08 for Pro/Pro genotype]. In cigarette smokers, the frequency of GSTP1 Ile/Ile genotype was higher in ESCC patients (OR 2.8, 95% CI 1.4-5.7). Among alcohol drinkers, borderline significance was also found for GSTP1 Ile/Ile genotype (OR 2.0, 95% CI 0.9-4.4). Results were not similar for the NAT2 genetic polymorphism. Using logistic analyses, we found that individuals with p53 Pro/Pro genotype had a significantly higher risk of developing ESCC than those with Arg/Arg genotype (OR 2.3, 95% CI 1. 1-5.1), after adjusting for other significant environmental risk factors. This result remained similar (OR 2.2, 95% CI 1.0-4.8 for p53 Pro/Pro vs. Arg/Arg), even after further adjustment for NAT2 and GSTP1 polymorphisms. The codon 72 p53 Pro/Pro genotype in the general population and GSTP1 Ile/Ile in cigarette smokers may predict a higher risk of developing ESCC.
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PMID:Genetic polymorphisms of p53 and GSTP1,but not NAT2,are associated with susceptibility to squamous-cell carcinoma of the esophagus. 1100 9


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