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 combination of psoralen and ultraviolet A radiation (PUVA) is widely used in the treatment of psoriasis. However, PUVA treatment increases the risk of developing skin cancer in psoriasis patients and induces skin cancer in mice. Since the DNA damage induced by PUVA is quite different from that induced by UV, we investigated whether PUVA-induced mouse skin cancers display carcinogen-specific mutations in the p53 tumor suppressor gene. The results indicated that 10 of 13 (77%) PUVA-induced skin tumors contained missense mutations predominantly at exons 6 and 7. In contrast, tumor-adjacent, PUVA-exposed skin from tumor-bearing animals did not exhibit p53 mutation in exons 4-8. Interestingly, about 40% of all mutations in PUVA-induced skin tumors occurred at 5'-TA sites, and an equal number of mutations occurred at one base flanking 5'TA or 5'-TAT sites. Since PUVA induces DNA cross-links exclusively at these sites and since UV "signature" mutations were rarely detected in PUVA-induced skin cancers, we can conclude that PUVA acts as a carcinogen by inducing unique PUVA signature mutations in p53. This finding may have implications for identifying the etiology of skin cancer in psoriasis patients who have undergone PUVA therapy.
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PMID:Signature p53 mutation at DNA cross-linking sites in 8-methoxypsoralen and ultraviolet A (PUVA)-induced murine skin cancers. 875 85

The clinical and pathologic features of a rare case of follicular carcinoma with small foci of poorly differentiated and anaplastic carcinoma are presented. Eight years after the removal of the primary neoplasm, the patient developed pulmonary and brain metastases that were predominantly composed of the poorly differentiated and anaplastic components. A comparative immunohistochemical and molecular analysis of p53 status in the follicular, poorly differentiated and anaplastic components of the tumor was performed. p53 immunostaining was restricted to the poorly differentiated and anaplastic areas. Single strand conformation polymorphism analysis (SSCP-PCR) from DNA obtained by microdissection demonstrated the presence of a mutation (TAT-->TGT; Tyr-->Cys) in codon 220, exon six of the p53 gene in the anaplastic component, that was absent in the well-differentiated follicular areas. The results of that study in this rare tumor support that p53 has a tumor progression role in thyroid tumorigenesis.
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PMID:p53 in a thyroid follicular carcinoma with foci of poorly differentiated and anaplastic carcinoma. 918 95

A 60-year-old woman was admitted in June 1993, because of anemia and purpura and given a diagnosis of acute myelogenous leukemia with trilineage dysplasia. She entered partial remission (PR) after three courses of low-dose Ara-C and G-CSF, but never reached complete remission (CR) in spite of additional chemotherapy. In October 1994, the number of leukocytes, myeloblasts, and erythroblasts in the patient's peripheral blood increased, and her clinical condition deteriorated. The disease was resistant to other therapy. The patient had pneumonia and died of septic shock in December 1994. A chromosomal analysis performed on admission showed 46,XX,t(3;5) (q21;q31) [9/9]. As an additional chromosomal abnormality, deletion of the X chromosome was observed in January, 1994. Analysis of the p53 gene by the polymerase chain reaction-single strand conformation polymorphism method showed one base transposition, from TAT to TGT (Tyr to Cys), at codon 220 of exon 6. Karyotype evolution and p53 gene mutation were observed during the disease course and may have been related to progression of the disease.
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PMID:[t(3;5) (q21;q31) chromosomal abnormality in a patient with acute myelogenous leukemia with trilineage myelodysplasia]. 979 99

We devised two short peptides corresponding to amino acids 211-221 of human Cdc25C fused with a part of HIV1-TAT. These peptides inhibited hChk1 and Chk2/HuCds1 kinase activity in vitro and specifically abrogated the G2 checkpoint in vivo. These peptides sensitized p53-defective cancer cell lines to DNA-damaging agent to death without obvious cytotoxic effect on normal cells. Our results clearly indicate that the specific abrogation of the cell cycle G2 checkpoint is a feasible strategy for cancer therapy, and hChk1 and Chk2/HuCds1 are proper targets for that purpose.
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PMID:Sensitization of cancer cells to DNA damage-induced cell death by specific cell cycle G2 checkpoint abrogation. 1060 29

Melatonin is a hormone with multiple functions in humans, produced by the pineal gland and stimulated by beta-adrenergic receptors. Melatonin has been shown to have radioprotection properties, but there has been little progress toward identifying the specific mechanisms of its action. To clarify the role of melatonin as a radioprotective compound, in response to X-ray irradiation, we investigated the effects of X-ray irradiation and melatonin on cytotoxicity, lipid peroxidation and alteration of the cell cycle in cultured skin fibroblast. An 8 Gy dose of X radiation resulted in cell death in 63% of irradiated cells, i.e. the cell viability was 37%. The damage was associated with lipid peroxidation of the cell membrane, as shown by the accumulation of malondialdehyde (MDA). By pre-incubation with melatonin (10(-5) M), a significant preventive effect was noted on the increase in the absolute number of surviving cells (up to 68% of cells were survived), and the levels of MDA were markedly decreased. These findings suggest a close correlation between an increase of lipid peroxidation and a rate of cell death. Morphological changes associated with apoptotic cell death were demonstrated by TEM. DNA flow-cytometry analysis revealed that X radiation increased pre-G1 apoptotic population by 7.6% compared to a very low level (1.3%) of non-irradiated cells. However, in the presence of melatonin, this apoptotic population decreased up to 4.5% at 10(-5) M. The p53 and p21 protein levels of skin fibroblasts increased 4 h after 8 Gy irradiation, but melatonin pretreatment did not change those levels. This study suggests that melatonin pretreatment inhibits radiation-induced apoptosis, and melatonin exerts its radioprotective effect by inhibition of lipid peroxidation and without any involvement of the p53/p21 pathway.
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PMID:Melatonin reduces X-ray irradiation-induced oxidative damages in cultured human skin fibroblasts. 1139 Feb 4

The tumour suppressor p53 is a multifunctional protein important for the maintenance of genomic integrity. It is able to form molecular complexes with different DNA targets and also with cellular proteins involved in DNA transcription and DNA repair. In mammalian cells the biochemical processing of DNA occurs on a nuclear sub-structure termed the nuclear matrix. Previously Deppert and co-workers have identified p53 in association with the nuclear matrix in viral- and non-viral transformed cell lines. In the present study we demonstrate, for the first time, that p53 is bound to the nuclear matrix in primary cultures of normal mammalian cells and that this binding increases following DNA damage. Analysis of cell lines expressing structural mutants of p53 revealed that association with the nuclear matrix is independent of the tertiary and quaternary structure of p53. However, the proline-rich domain towards the N-terminus of p53 (residues 67 to 98) appeared important for binding to the nuclear matrix. This was demonstrated by TET-ON regulated expression of p53-derived constructs in p53(-/-) murine embryonic fibroblasts (MEF p53(-/-)). The proline-rich domain of p53 has potential for SH3 protein-protein interaction, and has a role in p53-mediated apoptosis and possibly base excision repair of DNA damage. We discuss our observations in relation to the ability of p53 to facilitate DNA repair and also review evidence indicating that matrix-bound p53 in SV40-transformed cells may facilitate the transforming potential of SV40 large T antigen.
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PMID:p53 binds the nuclear matrix in normal cells: binding involves the proline-rich domain of p53 and increases following genotoxic stress. 1157 42

Two membrane transporters, the 17 amino acid (aa) oligopeptide penetratin derived from the homeodomain of Antennapedia (Ant) and an analogue of the basic domain of TAT (aa 47-57) (TAT-a) from HIV-1, were tested as carriers for a p53 C-terminal peptide (aa 361-382) into human breast cancer cells. The studies were performed to determine whether the membrane-transduction efficiency of membrane carriers: Ant, TAT or TAT analogue (TAT-a) correlated with peptide hydrophobic features. Peptide-sequence analysis clearly demonstrated that the Ant sequence and p53 peptide sequence (p53p) together created a peptide with enhanced hydrophobic characteristics; while the TAT or TAT analogue (TAT-a) and p53p sequence together created a peptide with significantly less hydrophobic qualities. The degree of hydrophobic moment and helical wheel plots for these peptides correlated directly with their ability to transduce the p53 peptide. Western blot analysis revealed that Ant was able to transduce p53 C-terminal peptide into human breast cancer cells as a highly efficient membrane transporter. Compared to Ant, TAT-a fused to the C-terminus of p53 peptide (p53p-TAT-a) was a less efficient carrier into these cells under the conditions of our study. Additionally, N-terminal linked TAT-a to p53p (TAT-a-p53p) showed even lower efficiency as a transporter than p53-TAT-a. Apoptosis assays showed that the p53 peptide, fused at its C-terminus to Ant (p53p-Ant), induced a higher percentage of apoptotic cells in human breast cancer cell lines expressing mutant or wild-type p53 as compared to p53 peptide fused at its C-terminus to the TAT-a sequence (p53p-TAT-a) or when fused at the N-terminus to TAT-a (TAT-a-p53p). These data suggested a direct correlation between hydrophobic characteristics and efficiency as a transporter. Sequence study, using hydrophobic moment and helical wheel analyses, may be useful predictive tools for choosing the best carrier for a peptide.
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PMID:Correlation between hydrophobic properties and efficiency of carrier-mediated membrane transduction and apoptosis of a p53 C-terminal peptide. 1241 61

Advanced-stage peritoneal carcinomatosis is resistant to current chemotherapy treatment and, in the case of metastatic ovarian cancer, results in a devastating 15%-20% survival rate. Therapeutics that restore genes inactivated during oncogenesis are predicted to be more potent and specific than current therapies. Experiments with viral vectors have demonstrated the theoretical utility of expressing the p53 tumor suppressor gene in cancer cells. However, clinically useful alternative approaches for introducing p53 activity into cancer cells are clearly needed. It has been hypothesized that direct reactivation of endogenous p53 protein in cancer cells will be therapeutically beneficial, but few tests of this hypothesis have been carried out in vivo. We report that a transducible D-isomer RI-TATp53C' peptide activates the p53 protein in cancer cells, but not normal cells. RI-TATp53C' peptide treatment of preclinical terminal peritoneal carcinomatosis and peritoneal lymphoma models results in significant increases in lifespan (greater than 6-fold) and the generation of disease-free animals. These proof-of-concept observations show that specific activation of endogenous p53 activity by a macromolecular agent is therapeutically effective in preclinical models of terminal human malignancy. Our results suggest that TAT-mediated transduction may be a useful strategy for the therapeutic delivery of large tumor suppressor molecules to malignant cells in vivo.
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PMID:Treatment of terminal peritoneal carcinomatosis by a transducible p53-activating peptide. 1496 35

Many conventional anticancer treatments kill cells irrespective of whether they are normal or cancerous, so patients suffer from adverse side effects due to the loss of healthy cells. Anticancer insights derived from cell cycle research has given birth to the idea of cell cycle G2 checkpoint abrogation as a cancer cell specific therapy, based on the discovery that many cancer cells have a defective G1 checkpoint resulting in a dependence on the G2 checkpoint during cell replication. Damaged DNA in humans is detected by sensor proteins (such as hHUS1, hRAD1, hRAD9, hRAD17, and hRAD26) that transmit a signal via ATR to CHK1, or by another sensor complex (that may include gammaH2AX, 53BP1, BRCA1, NBS1, hMRE11, and hRAD50), the signal of which is relayed by ATM to CHK2. Most of the damage signals originated by the sensor complexes for the G2 checkpoint are conducted to CDC25C, the activity of which is modulated by 14-3-3. There are also less extensively explored pathways involving p53, p38, PCNA, HDAC, PP2A, PLK1, WEE1, CDC25B, and CDC25A. This review will examine the available inhibitors of CHK1 (Staurosporin, UCN-01, Go6976, SB-218078, ICP-1, and CEP-3891), both CHK1 and CHK2 (TAT-S216A and debromohymenialdisine), CHK2 (CEP-6367), WEE1 (PD0166285), and PP2A (okadaic acid and fostriecin), as well as the unknown checkpoint inhibitors 13-hydroxy-15-ozoapathin and the isogranulatimides. Among these targets, CHK1 seems to be the most suitable target for therapeutic G2 abrogation to date, although an unexplored target such as 14-3-3 or the strategy of targeting multiple proteins at once may be of interest in the future.
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PMID:G2 checkpoint abrogators as anticancer drugs. 1507 95

Growth inhibition by transforming growth factor (TGF)-beta 1 has been attributed to the induction of cyclin-dependent kinase inhibitors, among which p21/Waf1 plays a major role in many biological contexts. In the present study, two new intracellular mediators for the induction of p21/Waf1 by TGF-beta 1 were identified in a human hepatocellular carcinoma cell line (JHH-5) expressing mutant-type p53. After addition of TGF-beta 1 to JHH-5 cells, a marked increase of the p21/Waf1 expression preceded the inhibition of DNA synthesis. Expression of IFN regulatory factor (IRF)-1, a known transacting factor for p21/Waf1 promoter, was elevated just before or in parallel with the increase of p21/Waf1. Transduction of antisense IRF-1 inhibited the increase in p21/Waf1 in JHH-5 cells treated with TGF-beta 1 and partially released the cells from the growth arrest by TGF-beta 1. Expression of S100C/A11, a member of the Ca(2+)-binding S100 protein family, also markedly increased after addition of TGF-beta 1. S100C/A11 protein was translocated to and accumulated in nuclei of TGF-beta 1-treated JHH-5 cells, where p21/Waf1 was concomitantly accumulated. When a recombinant S100C/A11 protein was introduced into nuclei of JHH-5 cells, DNA synthesis was markedly inhibited in a dose-dependent manner in the absence of TGF-beta 1. Prior transfection of p21/Waf1-targeted small interfering RNA efficiently blocked decrease of DNA synthesis in JHH-5 cells caused by TAT-S100C/A11 or TGF-beta 1 and markedly inhibited expression of p21/Waf1 protein in the cells. These results indicate that IRF-1 and S100C/A11 mediate growth inhibition by TGF-beta 1 via induction of p21/Waf1.
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PMID:Involvement of interferon regulatory factor 1 and S100C/A11 in growth inhibition by transforming growth factor beta 1 in human hepatocellular carcinoma cells. 1520 26


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