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)

A substantial portion of patients with estrogen receptor-positive breast cancer fail to respond to estrogen depletion or to the antiestrogen tamoxifen. The molecular changes that lead to tamoxifen resistance and estrogen-independent growth are unknown. To test the hypothesis that a p53 mutation could result in tamoxifen resistance and estrogen-independent growth, the MCF-7 cell line was transfected with p53 cDNA which was mutated at codon 179 (histidine to glutamine). MCF-7 is an estrogen receptor-positive, estrogen-dependent, tamoxifen-sensitive cell line with only wild-type p53. The presence of transfected mutant p53 cDNA was verified by the PCR, and overexpression of p53 protein was assessed by Western blotting. Five separate mutant-transfected clones were selected and tested in subsequent growth experiments. In monolayer culture, there was no consistent evidence of estrogen-independent growth or tamoxifen resistance in the mutant transfectants compared with vector-only controls or the parental cell line. In soft agar growth experiments, four of five mutant transfectants remained sensitive to tamoxifen in a dose-dependent manner. In the presence of wild-type p53, mutant 179 p53 protein does not result in estrogen-independent growth or tamoxifen resistance. These results do not exclude the possibility that other p53 mutational types could result in tamoxifen resistance, or that loss of the remaining wild-type allele may be necessary to result in this phenotype.
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PMID:p53 mutation and tamoxifen resistance in breast cancer. 981 13

We found previously that restriction of tyrosine (Tyr) and phenylalanine (Phe) inhibited growth and metastasis of B16BL6 murine melanoma and arrested these cells in the G0-G1 phase of the cell cycle. Here, we report that deprivation of these two amino acids in vitro induces apoptosis in B16BL6 and in human A375 melanoma cells but not in nontransformed, neonatal murine epidermal cells or human infant foreskin fibroblasts. Four days after deprivation of Tyr and Phe in vitro, 37% of B16BL6 and 51% of A375 melanoma cells were undergoing apoptosis. Apoptosis was not associated with elevation in intracellular calcium or alteration in p53 or c-myc protein expression. Expression and Tyr phosphorylation of focal adhesion kinase (FAK) were inhibited in both melanoma cell lines by deprivation of Tyr and Phe but not by deprivation of glutamine or serum. Tyr phosphorylation of FAK in Tyr- and Phe-deprived melanoma cells was enhanced within 30 min of refeeding with complete DMEM. FAK protein expression recovered within 60 min, and cell viability recovered within 24 h. Genistein, a tyrosine kinase inhibitor that specifically inhibits Tyr phosphorylation of FAK, did not induce apoptosis in A375 melanoma cells at a concentration of 50 microM. Genistein prevented the recovery of cell viability upon refeeding with Tyr and Phe to previously deprived A375 melanoma cells. These data collectively indicate that apoptosis induced by Tyr and Phe deprivation is FAK-dependent.
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PMID:Focal adhesion kinase-dependent apoptosis of melanoma induced by tyrosine and phenylalanine deficiency. 997 29

p73 is a recently cloned tumor suppressor gene that is highly homologous to p53, and the products of both possess similar functions in inhibiting cell growth and inducing apoptosis. Interestingly, the COOH-terminal region of p53 displays no significant homology with that of p73. Moreover, p73 has an additional segment at its COOH terminus. Recently, we have found two mutations of p73 with amino acid substitution (P405R and P425L) in primary neuroblastomas. Because the region (amino acid residues 382-491) contains a glutamine- and proline-rich domain, we hypothesized that it has a transactivation function, and the mutations found in tumors result in loss of function. To test it, we used the yeast GAL4 DNA-binding fusion system. Yeast transformants expressing a GAL4-p73(1-112) or a GAL4-p73alpha(380-513) fusion protein were grown in SD medium lacking histidine and tryptophan and exhibited a significant induction of beta-galactosidase activity. Transient transfection experiments revealed that both of fusion proteins could induce the chloramphenicol acetyltransferase activity in mammalian cells, indicating that the COOH-terminal as well as NH2-terminal regions of p73 had significantly high levels of transactivation activity. Furthermore, the former activity was severely impaired in two naturally occurring mutant forms found in neuroblastomas. These suggest that, unlike p53, p73 has two domains with transactivation function, one in the NH2-terminal region and the other in the COOH-terminal region. Loss of function mutation in the latter might be involved in tumorigenesis and/or tumor progression.
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PMID:Identification of a transactivation activity in the COOH-terminal region of p73 which is impaired in the naturally occurring mutants found in human neuroblastomas. 1038 37

The cell cycle inhibitor protein p21(WAF1/Cip1) (p21) is a critical downstream effector in p53-dependent mechanisms of growth control and p53-independent pathways of terminal differentiation. We have recently reported that the transforming growth factor-beta pathway-specific Smad3 and Smad4 proteins transactivate the human p21 promoter via a short proximal region, which contains multiple binding sites for the ubiquitous transcription factor Sp1. In the present study we show that the Sp1-occupied promoter region mediates transactivation of the p21 promoter by c-Jun and the related proteins JunB, JunD, and ATF-2. By using gel electrophoretic mobility shift assays we show that this region does not contain a binding site for c-Jun. In accordance with the DNA binding data, c-Jun was unable to transactivate the p21 promoter when overexpressed in the Sp1-deficient Drosophila-derived SL2 cells. Coexpression of c-Jun and Sp1 in these cells resulted in a strong synergistic transactivation of this promoter. In addition, a chimeric promoter consisting of six tandem high affinity Sp1-binding sites fused with the CAT gene was transactivated by overexpressed c-Jun in HepG2 cells. The above data propose functional cooperation between c-Jun and Sp1. Physical interactions between the two factors were demonstrated in vitro by using GST-Sp1 hybrid proteins expressed in bacteria and in vitro transcribed-translated c-Jun. The region of c-Jun mediating interaction with Sp1 was mapped within the basic region leucine zipper domain. In vivo, functional interactions between c-Jun and Sp1 were demonstrated using a GAL4-based transactivation assay. Overexpressed c-Jun transactivated a chimeric promoter consisting of five tandem GAL4-binding sites only when coexpressed with GAL4-Sp1-(83-778) fusion proteins in HepG2 cells. By utilizing the same assay, we found that the glutamine-rich segment of the B domain of Sp1 (Bc, amino acids 424-542) was sufficient for c-Jun-induced transactivation of the p21 promoter. In conclusion, our data support a mechanism of superactivation of Sp1 by c-Jun, which is based on physical and functional interactions between these two transcription factors on the human p21 and possibly other Sp1-dependent promoters.
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PMID:c-Jun transactivates the promoter of the human p21(WAF1/Cip1) gene by acting as a superactivator of the ubiquitous transcription factor Sp1. 1050 25

After the Chernobyl accident in 1986, there was a significant increase in the incidence of papillary thyroid carcinoma in fallout-exposed children from Belarus. We studied the p53 gene from 24 papillary thyroid carcinoma cases presenting in 1996. All subjects lived in contaminated regions of Belarus at the time of the accident and were under age 20 when exposed to fallout. Exons 5 through 9 of p53 were amplified from genomic tumor DNA using the polymerase chain reaction (PCR). The PCR products were analyzed by direct DNA sequencing using an automated sequencer. Five cases each exhibited two molecular alterations within exon 5. Alterations were confirmed by sequencing in both directions. One alteration, involving codon 167 (CAG-->CAT) in all five cases, resulted in the substitution of HIS for GLN. The second alteration, involving codon 183 (TCA-->TGA) in all five cases, resulted in a premature termination codon. Leukocyte DNA from each of the positive cases was analyzed and found to contain only wild-type p53 sequence. These results suggest that mutations involving codons 167 and 183 in the p53 locus are important in the pathogenesis of a subset (21%) of radiation-induced papillary thyroid carcinomas from Belarus.
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PMID:Molecular alterations involving p53 codons 167 and 183 in papillary thyroid carcinomas from chernobyl-contaminated regions of belarus. 1069 10

Some six or so physiological systems, essential to normal mammalian life, are involved in poisoning; an intoxication that causes severe injury to any one of them could be life threatening. Reversible chemical reactions showing Scatchard-type binding are exemplified by CO, CN- and cyclodiene neurotoxin insecticide intoxications, and by antigen-antibody complex formation. Haemoglobin (Hb) molecular biology accounts for the allosteric co-operativity and other characteristics of CO poisoning, CN- acts as a powerful cytochrome oxidase inhibitor, and antigen binding in a deep antibody cleft between two domains equipped with epitopes for antigen-binding groups explains hapten-specific immune reactions. Covalent chemical reactions with second-order (SN2) kinetics characterize Hg and Cd poisonings, the reactions of organophosphates and phosphonates with acetylcholinesterase and neurotoxic esterase and the reaction sequence whereby Paraquat accepts electrons and generates superoxide under aerobic conditions. Indirect carcinogens require cytochrome P450 activation to form DNA adducts in target-organ DNA and cause cancer, but a battery of detoxifying enzymes clustered with the P450 system must be overcome. Thus, S-metabolism competes ineffectively with target DNA for reactive vinyl chloride (VC) metabolites, epoxide hydrolase is important to the metabolism and carcinogenicity of alfatoxins and polycyclic aromatic hydrocarbons (benzo[a]pyrene, etc.), and the non-toxic 2-naphthylhydroxylamine N-glucuronide acts as a transport form in 2-naphthylamine bladder cancer. VC liver-cancer pathogenesis is explicable in terms of the presence of the glutathione S-transferase detoxifying system in hepatocytes and its absence from the fibroblastic elements, and of the VC concentrations reaching the liver by different administrative routes. In VC carcinogenicity, chemical reactions give imidazo-cyclization products with nucleoside residues of target DNA, and in benzene leukaemia, Z,Z-muconaldehyde forms cyclic products containing a pyrrole residue linked to purine. Increased HbCO concentrations reduce the O2-carrying capacity of the blood, and the changed shape of the O2-Hb dissociation curve parallels disturbance in O2 unloading. CN- acts on electron transport and paralyses respiration. In telodrin poisoning, preconvulsive glutamine formation abstracts tricarboxylic acid intermediates incommensurately with normal cerebral respiration. Antigen-antibody complexing depletes the antibody titre, available against infection. At high doses of Cd, Cd-thionein filtered through the kidneys is reabsorbed and tubular lesions produced. Some organophosphate insecticides promote irreversible acetylcholinesterase phosphorylation and blockade nerve function, and others react with neurotoxic esterase to cause delayed neuropathy. The evidence for Paraquat pulmonary poisoning suggests a radical mechanism involving three interrelated cyclic reaction stages. The action of N- and O8 (O substituent in 6-position of the purine) demethylases explains deletion mechanisms for DNA-alkyl adducts. DNA-directed synthesis in the presence of ultimate carcinogens provides for an estimation of misincorporations, which implicate the same transversions as those found by direct mutagenicity testing. Chemical carcinogens recognize tissue-sensitive cells and modify their heritable genetic complement. Oncoproteins encoded by activated oncogenes signal the transformation of normal cells into cancer cells. The importance of the H-ras oncogene and p53 tumour-suppressor gene is stressed. Antidotal action is analysed; for example, parenteral glutamine administration to telodrin-intoxicated rats restores the depleted cerebral glutamate level and prevents seizures. Glutamate acts as anticonvulsant in petit mal epilepsy. In general, therefore, the reaction of the toxicant-related substance with the relevant target-tissue macromolecule accounts for the biochemical/biological events at a cellular level a
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PMID:Toxic action/toxicity. 1074 Aug 94

While the mechanisms of tumorigenesis for adrenocortical neoplasms remain unknown, several genes, such as Gsalpha, ACTH receptor (MC2-R), p53, and p16 tumor suppressor genes, are considered to be candidates for adrenocortical neoplasms. Mutation analysis studies have documented these genes in adrenocortical neoplasms, but these studies focused on the mutation of only one of these genes. In the present study we examined the mutations of three of these genes (Gsalpha, MC2-R, and p53) in adrenocortical neoplasms in Japanese patients. We amplified these genes using polymerase chain reaction and directly sequenced them in 30 functioning adrenocortical neoplasms. As for Gsalpha, we identified a heterogeneous substitution of glutamine to histidine at codon 227 and a gain of an Nru I restriction endonuclease site. The mutation was restricted to adenomatous tissue, and did not occur in the adjacent normal adrenal tissue or leukocytes of the patient. We did not find any mutations in MC2-R and p53. In conclusion, although the contribution of these three genes to adrenocortical tumorigenesis remains to be determined, it is suggested that the mutation of Gsalpha might play a role in functional adrenocortical neoplasms.
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PMID:Mutation analysis of Gsalpha, adrenocorticotropin receptor and p53 genes in Japanese patients with adrenocortical neoplasms: including a case of Gsalpha mutation. 1107 27

Lengthening a glutamine tract in huntingtin confers a dominant attribute that initiates degeneration of striatal neurons in Huntington's disease (HD). To identify pathways that are candidates for the mutant protein's abnormal function, we compared striatal cell lines established from wild-type and Hdh(Q111) knock-in embryos. Alternate versions of full-length huntingtin, distinguished by epitope accessibility, were localized to different sets of nuclear and perinuclear organelles involved in RNA biogenesis and membrane trafficking. However, mutant STHdh(Q111) cells also exhibited additional forms of the full-length mutant protein and displayed dominant phenotypes that did not mirror phenotypes caused by either huntingtin deficiency or excess. These phenotypes indicate a disruption of striatal cell homeostasis by the mutant protein, via a mechanism that is separate from its normal activity. They also support specific stress pathways, including elevated p53, endoplasmic reticulum stress response and hypoxia, as potential players in HD.
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PMID:Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells. 1109 56

Expansion of CAG repeats within the coding region of target genes is the cause of several autosomal dominant neurodegenerative diseases including Huntington's disease (HD). A hallmark of HD is the proteolytic production of N-terminal fragments of huntingtin containing polyglutamine repeats that form ubiquitinated aggregates in the nucleus and cytoplasm of the affected neurons. In this study, we used an ecdysone-inducible stable mouse neuro2a cell line that expresses truncated N-terminal huntingtin (tNhtt) with different polyglutamine length, along with mice transgenic for HD exon 1, to demonstrate that the ubiquitin-proteasome pathway is involved in the pathogenesis of HD. Proteasomal 20S core catalytic component was redistributed to the polyglutamine aggregates in both the cellular and transgenic mouse models. Proteasome inhibitor dramatically increased the rate of aggregate formation caused by tNhtt protein with 60 glutamine (60Q) repeats, but had very little influence on aggregate formation by tNhtt protein with 150Q repeats. Both normal and polyglutamine-expanded tNhtt proteins were degraded by proteasome, but the rate of degradation was inversely proportional to the repeat length. The shift of the proteasomal components from the total cellular environment to the aggregates, as well as the comparatively slower degradation of tNhtt with longer polyglutamine, decreased the proteasome's availability for degrading other key target proteins, such as p53. This altered proteasomal function was associated with disrupted mitochondrial membrane potential, released cytochrome c from mitochondria into the cytosol and activated caspase-9- and caspase-3-like proteases. These results suggest that the impaired proteasomal function plays an important role in polyglutamine protein-induced cell death.
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PMID:Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. 1133 15

Transglutaminases catalyze the posttranslation modification of proteins by catalyzing Ca2+ dependent acyl-transfer reaction resulting in the formation of new g-amide bonds between g-carboxamide groups of peptide-bound glutamine residues and various primary amines. Such glutamine residue serves as acyl-donor and the most common acyl-acceptors are e-amino groups of peptide-bound lysine residues or primary amino groups of some naturally occurring polyamines, like putrescine or spermidine. The active site of cysteine reacts first with the g-carboxamide group of glutamine residue to form the acyl-enzyme intermediate under the release of ammonia. In the second step, the complex reacts with a primary amine to form an isopeptide bond and liberate the reactivated enzyme. The presence of transglutaminases has been observed in various endocrine glands such as human pituitary, which was investigated by immunohistochemical methods using specific antibodies. A significant increase in the expression and activity of tissue transglutaminase was observed during involution of thymus. In the genital tract of the male rat two different forms of the enzyme transglutaminase could be identified and characterized. the presence of p53 and tissues transglutaminase gene expressions in human normal and pathologic adrenal tissues. The Ca2+-responsive enzyme transglutaminase, which catalyzes the cross-bridging of proteins, was found in pancreatic islet cells.
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PMID:Transglutamines and endocrine system (minireview). 1197 49


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