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 past year has seen the determination of over three dozen new structures of DNA-binding proteins. Highlights of new structural motifs include the DNA-binding domain of p53 tumor suppressor and the amino-terminal fragment of Escherichia coli DNA topoisomerase I. Other structures illustrate variations of known structural motifs, including co-crystals of helix-turn-helix, basic helix-loop-helix, and zinc finger proteins.
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PMID:Structure and function of DNA-binding proteins. 761 87

beta-Lapachone, a plant product, has been shown to be a novel inhibitor of DNA topoisomerase I, with a mode of action different from camptothecin and a chemical structure distinct from those of current anti-cancer drugs. We observed that beta-lapachone, at concentrations of less than 8 microM, induces cell death with characteristics of apoptosis in human prostate cancer cell lines. This effect of beta-lapachone was also observed in a human promyelocytic leukemia cell line (HL-60). beta-Lapachone-induced apoptosis is independent of p53 expression, and ectopic overexpression of bcl-2 did not confer significant resistance to beta-lapachone. Among other human carcinoma and adenoma cell lines tested, human breast and ovary carcinoma showed sensitivity to the cytotoxic effect of beta-lapachone without manifesting signs of apoptosis. These results suggest that beta-lapachone is a potential compound to be added to cancer chemotherapy, particularly for prostate cancer.
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PMID:Induction of apoptosis by beta-lapachone in human prostate cancer cells. 764 Nov 81

Chemosensitivity of B lymphocytes, obtained from 65 patients with B-cell chronic lymphocytic leukemia (B-CLL), Rai stages 0 through IV, was determined using the MTT assay. The results were expressed by the drug concentration required for 50% inhibition of cell viability (IC50). The cytotoxicity of chlorambucil (CLB) was compared with that of fludarabine and the DNA topoisomerase I inhibitors, camptothecin, 9-aminocamptothecin, 10,11-methylenedioxy-20(S)-camptothecin (10,11-MDC) and 9-amino-10,11-methylenedioxy-20(S)-campthothecin (9-A-10,11-MDC), and topotecan. Considerable heterogeneity in sensitivity to CLB was observed, with a median IC50 of 40.5 mumol/L in untreated patients. B-CLL cells from patients treated with CLB had a significantly higher median IC50 of 86.0 mumol/L (P < .01). Untreated as well as CLB-treated patients were divided into two subsets. For the purpose of this study, B-CLL lymphocytes with an IC50 CLB of less than 61.0 mumol/L were designated as "sensitive" and those with an IC50 CLB of > or = 61.0 mumol/L were designated as "resistant." After baseline assays, 15 untreated patients received CLB; after treatment, the IC50 increased in B-CLL lymphocytes from 13 of 15 patients. The response to CLB treatment, determined by its effect on the absolute lymphocyte count and by the Eastern Cooperative Oncology Group clinical criteria, was significantly better in patients whose lymphocytes had an IC50 CLB of less than 61.0 mumol/L before therapy (P < .01). B-CLL lymphocytes also had a variable degree of sensitivity in vitro to each of the other drugs. There was significant cross-resistance between CLB and fludarabine (P < 0.01). Whereas only 29% of CLB-resistant B-lymphocyte specimens obtained from individual patients were sensitive to fludarabine in vitro, 52% and 67% of CLB-resistant lymphocyte samples were sensitive to 10,11-MDC and 9-A-10,11-MDC, respectively. We have previously reported that p53 gene mutations were associated with aggressive B-CLL and a poor prognosis. B lymphocytes from seven patients with these mutations were resistant to CLB, and five of six were resistant to fludarabine. Lymphocytes from four of seven were resistant to 10,11-MDC, and three of four were resistant to 9-A-10,11-MDC. This study implies that the MTT assay may be useful in identifying subsets of CLL patients resistant to conventional chemotherapy. However, definitive conclusions can not be drawn in view of the small number of patients studied prospectively. In addition, these results suggest the potential of camptothecin-based therapy for patients unresponsive to standard treatment.
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PMID:Chemosensitivity of lymphocytes from patients with B-cell chronic lymphocytic leukemia to chlorambucil, fludarabine, and camptothecin analogs. 794 99

Camptothecin (CPT) traps covalent DNA topoisomerase I-linked DNA single-strand breaks (cleavable complexes). To determine the differences in DNA damage signalling leading to differential sensitivity to CPT, two human colon cancer cell lines, SW620 and KM12, with nonfunctional p53 and the same level of topoisomerase I cleavable complex formation but differential sensitivity to CPT (Cancer Res. 56:4430-7; 1996) were studied. The levels of mRNA expression of DNA damage-inducible or death-related genes were measured at different times after CPT treatment. KM12 cells exhibited 3-fold higher basal levels of BCL-2 mRNA. Consistently, secondary DNA fragmentation, quantitated using a filter elution assay, was detected 24 h later and was 2-4-fold lower in KM12 cells than in SW620 cells. No induction of BAX was detected in either cell line. Consistent with the absence of functional p53, p21CIP1/WAF1 and GADD45 genes were not induced within the first 24 h. However, in SW620 cells, both mRNA levels were increased more than 10-fold at 48 h. The BCL-2-related gene MCL-1 and topoisomerase II mRNA were induced at 24 h, and topoisomerase I mRNA levels increased 3-fold at 48 h, only in SW620 cells. We conclude that cellular response to CPT-induced DNA damage can involve p53-independent pathways leading to the induction of p53-effector genes. Induction of these genes at the onset of apoptosis is associated with CPT sensitivity.
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PMID:Differential GADD45, p21CIP1/WAF1, MCL-1 and topoisomerase II gene induction and secondary DNA fragmentation after camptothecin-induced DNA damage in two mutant p53 human colon cancer cell lines. 893 95

Recently, natural product DNA topoisomerase I inhibitors 10-hydroxycamptothecin (HCPT) and camptothecin (CPT) have been shown to have therapeutic effects in both in vitro and in vivo models of human breast cancer. In the present study, we characterized the in vitro and in vivo apoptotic pathways induced by HCPT and CPT in the human breast cancer cell lines MCF-7 and MDA-MB-468. Using various DNA fragmentation analyses and the terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay, the apoptosis induced by HCPT and CPT was shown to be dose- and time-dependent. The MDA-MB-468 cells were more sensitive to both HCPT and CPT than MCF-7 cells. HCPT induced apoptosis in MDA-MB-468 cells more effectively than CPT; however, in MCF-7 cells, CPT was more effective than HCPT. The levels of p53 and p21WAF1/CIP1 protein increased in MCF-7 cells treated with HCPT or CPT in a dose- and time-dependent manner. The levels of p21WAF1/CIP1 protein also increased in a dose- and time-dependent manner in MDA-MB-468 cells treated with HCPT or CPT, whereas the mutated p53 protein levels had no significant change. The elevation of p53 protein levels in MCF-7 cells treated with CPT was significantly inhibited by preincubation with DNA breaks inhibitor aphidicolin, while the elevation of p21WAF1/CIP1 protein levels was not inhibited. The elevation of p21WAF1/CIP1 in MDA-MB-468 cells treated with CPT was not inhibited by aphidicolin. Using Northern blot analysis, the transcription of p21WAF1/CIP1 was shown to increase in a dose-dependent manner in MCF-7 and MDA-MB-468 cells treated with HCPT or CPT. These results suggest that treatment with HCPT and CPT results in increased levels of p21WAF1/CIP1 protein and mRNA, and that they induce apoptosis in human breast cancer cells through both p53-dependent and -independent pathways. These findings may be significant in further understanding the mechanisms of actions of camptothecins in the treatment of human cancers.
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PMID:Upregulation of p21WAF1/CIP1 in human breast cancer cell lines MCF-7 and MDA-MB-468 undergoing apoptosis induced by natural product anticancer drugs 10-hydroxycamptothecin and camptothecin through p53-dependent and independent pathways. 949 38

Protein phosphorylation plays an important role in signal transduction, but its involvement in apoptosis still remains unclear. In this report, the p53-null human leukemia HL60 cells were used to investigate phosphorylation and degradation of lamin B during apoptosis. We found that lamin B was phosphorylated within 1 h after addition of the DNA topoisomerase I inhibitor, camptothecin, and that lamin B phosphorylation preceded lamin B degradation and DNA fragmentation. Using a cell-free system we also found that cytosol from camptothecin-treated cells induced lamin B phosphorylation and degradation in isolated nuclei from untreated HL60 cells. Lamin B phosphorylation was prevented by the protein kinase C (PKC) inhibitor 7-hydroxystaurosporine (UCN-01) but not by the Cdc2 inhibitor, flavopiridol. Phosphorylation of lamin B was inhibited by immunodepletion of PKCalpha from activated cytosol and was restored by addition of purified PKCalpha. PKCalpha activity also increased rapidly as lamin B was phosphorylated after initiation of the apoptotic response in HL60 cells. These data suggest that lamin B is phosphorylated by PKCalpha and proteolyzed before DNA fragmentation in HL60 cells undergoing apoptosis.
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PMID:Lamin B phosphorylation by protein kinase calpha and proteolysis during apoptosis in human leukemia HL60 cells. 953 42

Segmental jumping translocations are chromosomal abnormalities in treatment-related leukemias characterized by multiple copies of the ABL and/or MLL oncogenes dispersed throughout the genome and extrachromosomally. Because gene amplification potential accompanies loss of wild-type p53, we examined the p53 gene in a case of treatment-related acute myeloid leukemia (t-AML) with MLL segmental jumping translocation. The child was diagnosed with ganglioneuroma and embryonal rhabdomyosarcoma (ERMS) at 2 years of age. Therapy for ERMS included alkylating agents, DNA topoisomerase I and DNA topoisomerase II inhibitors, and local radiation. t-AML was diagnosed at 4 years of age. The complex karyotype of the t-AML showed structural and numerical abnormalities. Fluorescence in situ hybridization analysis showed multiple copies of the MLL gene, consistent with segmental jumping translocation. A genomic region including CD3, MLL, and a segment of band 11q24 was unrearranged and amplified by Southern blot analysis. There was no family history of a cancer predisposing syndrome, but single-strand conformation polymorphism (SSCP) analysis detected identical band shifts in the leukemia, ganglioneuroma, ERMS, and normal tissues, consistent with a germline p53 mutation, and there was loss of heterozygosity in the ERMS and the t-AML. Sequencing showed a CGA-->TGA nonsense mutation at codon 306 in exon 8. The results of this analysis indicate that loss of wild-type p53 may be associated with genomic instability after DNA-damaging chemotherapy and radiation, manifest as a complex karyotype and gene amplification in some cases of t-AML.
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PMID:Association of germline p53 mutation with MLL segmental jumping translocation in treatment-related leukemia. 961 38

New anticancer drugs that target DNA topoisomerase I (topo I) are showing activity against a wide variety of solid human neoplasms. These drugs work by a novel mechanism of action and cause topo I-mediated DNA breaks. These DNA breaks become lethal in cycling cells when they interact with the replication fork. Because of the challenges in treating metastatic malignant melanoma, we performed an immunohistochemical study of this group of neoplasms to search for the presence of molecular markers that might indicate tumor response to topo I active drugs. Using a new immunohistochemical stain for topo I, we found elevation of this protein in 10 of 24 cases (41.6%) of metastatic malignant melanoma. The metastatic tumors that showed increased expression of topo I (2+ or 3+) had statistically significant higher proliferation indices, measured by immunohistochemical staining for DNA topo II-alpha, than did metastatic lesions with no detectable topo I expression. The average topo II-alpha index of metastatic melanomas with 2+ topo I expression was 45.1 (SD = 17.9) and with 3+ topo I expression was 52.3 (SD = 32.5). These values were found to be statistically different (P = .05) than the average topo II-alpha index of 18.9 (SD = 17.7) found for metastatic melanomas without detectable topo I immunostaining. Immunohistochemical staining for p53 suggested abnormal p53 function in 6 of the 10 melanomas (60%), which showed elevations of topo I (2 to 3+ topo I immunostaining) but normal p53 function in all 14 metastatic lesions that showed normal topo I expression.
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PMID:Expression of DNA topoisomerase I, DNA topoisomerase II-alpha, and p53 in metastatic malignant melanoma. 982 1

DNA topoisomerase I (topo I) is the molecular target of the camptothecin group of antitumor drugs. Laboratory studies have indicated that cells sensitive to these drugs contain elevated levels of topo I. In this study, we immunostained 49 cases of transitional cell carcinoma from the urinary bladder with a monoclonal antibody directed against human topo I. We found elevated expression of the enzyme in 77% (38 of 49). This included three of six grade I tumors (50%), 9 of 15 grade II tumors (60%), 14 of 15 grade III tumors (93%) and 12 of 13 grade IV tumors (92%). Because the number of cycling cells in a tumor also may be an important determinant of topo I drug response, a proliferation index (topo II-alpha) also was performed for each case. The average topo II-alpha index of grade I tumors was 7.5 x 3.8; for grade II tumors, 20.1+/-10.5; for grade III tumors, 40.3 x 8.2; and for grade IV tumors, 50.5+/-13.0. Because a functional p53 tumor suppressor gene may be necessary for anticancer drug response, we also evaluated our cases for alteration in p53 function. Mutations in the p53 tumor suppressor gene, estimated by immunohistochemical staining, were common, occurring in 23 of 49 cases (47%). The number of cases with elevated topo I, a large growth fraction, and a functional p53 tumor suppressor gene was 4 of 49 (8%). Our results suggest that a small population of patients with transitional cell carcinoma of the urinary bladder may have tumors with molecular features suggesting responsiveness to the new anticancer drugs targeting topo I.
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PMID:Elevations of DNA topoisomerase I in transitional cell carcinoma of the urinary bladder: correlation with DNA topoisomerase II-alpha and p53 expression. 1020 58

DNA topoisomerase I is a nuclear enzyme involved in transcription, recombination, and DNA damage recognition. Previous studies have shown that topoisomerase I interacts directly with the tumor-suppressor protein p53. p53 is a transcription factor that activates certain genes through binding to specific DNA sequences. We now report that topoisomerase I can be stimulated by both latent and activated wild-type p53 as well as by several mutant and truncated p53 proteins in vitro, indicating that sequence-specific DNA-binding and stimulation of topoisomerase I are distinct properties of p53. These assays also suggest that the binding site for topoisomerase I on p53 is between amino acids 302 and 321. In living cells, the interaction between p53 and topoisomerase I is strongly dependent on p53 status. In MCF-7 cells, which have wild-type p53, the association between the two proteins is tightly regulated in a spatial and temporal manner and takes place only during brief periods of genotoxic stress. In marked contrast, the two proteins are constitutively associated in HT-29 cells, which have mutant p53. These findings have important implications for both cellular stress response and genomic stability, given the ability of topoisomerase I to recognize DNA lesions as well as to cause illegitimate recombination.
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PMID:The interaction between p53 and DNA topoisomerase I is regulated differently in cells with wild-type and mutant p53. 1046 12


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