Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Programmed cell death (apoptosis) is a normal physiological process, which could in principle be manipulated to play an important role in cancer therapy. The key importance of p53 expression in the apoptotic response to DNA-damaging agents has been stressed because mutant or deleted p53 is so common in most kinds of cancer. An important strategy, therefore, is to find ways to induce apoptosis in the absence of wild-type p53. In this paper, we compare apoptosis in normal human mammary epithelial cells, in cells immortalized with human papilloma virus (HPV), and in mammary carcinoma cell lines expressing wild-type p53, mutant p53, or no p53 protein. Apoptosis was induced with mitomycin C (MMC), a DNA cross-linking and damaging agent, or with staurosporine (SSP), a protein kinase inhibitor. The normal and HPV-transfected cells responded more strongly to SSP than did the tumor cells. After exposure to MMC, cells expressing wild-type p53 underwent extensive apoptosis, whereas cells carrying mutated p53 responded weakly. Primary breast cancer cell lines null for p53 protein were resistant to MMC. In contrast, two HPV immortalized cell lines in which p53 protein was destroyed by E6-modulated ubiquitinylation were highly sensitive to apoptosis induced by MMC. Neither p53 mRNA nor protein was induced in the HPV immortalized cells after MMC treatment, although p53 protein was elevated by MMC in cells with wild-type p53. Importantly, MMC induced p21 mRNA but not p21 protein expression in the HPV immortalized cells. Thus, HPV 16E6 can sensitize mammary epithelial cells to MMC-induced apoptosis via a p53- and p21-independent pathway. We propose that the HPV 16E6 protein modulates ubiquitin-mediated degradation not only of p53 but also of p21 and perhaps other proteins involved in apoptosis.
 ...
PMID:The human papilloma virus 16E6 gene sensitizes human mammary epithelial cells to apoptosis induced by DNA damage. 764

The temperature-sensitive mutant p53 tsp53val135 (tsp53) displays a mutant phenotype at 38 degrees C, but assumes properties of a wild-type (wt) p53 at 32 degrees C. We analysed the cellular responses of two cell lines which ectopically overexpress tsp53, and dramatically differ in their responses to tsp53 expressed at 32 degrees C. Clone 6 (cl6) cells [precrisis rat embryo fibroblasts transformed by tsp53val135 and an activated ras oncogene at 38 degrees C (Michalovitz et al., 1990. Cell 62, 671-680) stop to grow and arrest mainly in the G1 phase of the cell cycle, whereas MethAp53ts cells [BALB/c mouse MethA tumor cells, transfected with the same tsp53 encoding vector as cl6 cells (Otto and Deppert, 1993. Oncogene 8, 2591-2603)] do not growth arrest at 32 degrees C. Both cell lines expressed similar amounts of tsp53, which was mainly cytoplasmic at 38 degrees C and mainly nuclear at 32 degrees C. At 32 degrees C, both cell lines contained similar amounts of waf1/cip1 mRNA. However, the amount of mdm2 mRNA in MethAp53ts cells was considerably higher compared to that in cl6 cells. The different transcriptional regulation of the mdm2-gene in cl6 and MethAp53ts cells at 32 degrees C indicated that the tsp53 proteins in these cells were functionally different. This assumption was supported by our finding that at 32 degrees C phosphorylation of the tsp53 in these cells was markedly different. We conclude that the cellular environment is an important determinant of p53 function.
 ...
PMID:Cell-specific transcriptional activation of the mdm2-gene by ectopically expressed wild-type form of a temperature-sensitive mutant p53. 765 32

Several groups have recently isolated and characterized an inhibitor of cyclin-dependent kinases, p21CIP1/WAF1 which is transcriptionally induced by wild-type but not mutant p53. It is likely that p21CIP1/WAF1 mediates the growth suppression effects of p53 by arresting the cell cycle at the G1/S checkpoint, and by inducing apoptosis. To test the hypothesis that primary human tumors have mutations in the CIP1/WAF1 gene which propagates the carcinogenic process, we examined primary breast and sarcoma tumor specimens for alterations in the CIP1/WAF1 gene. Unique, or acquired somatic mutations were not observed indicating that they are not selected for during the carcinogenic process; however, two common variants were identified. The variants were not unique to tumors as 10.7% of normal individuals exhibited the variants. Nonetheless, the frequency of the variants in tumors with wild-type p53 (20.4%) was significantly greater (p = 0.05) than in normal DNAs. In contrast, the frequency of the variants (4.1%) was found to be significantly lower in tumors with p53 mutations (p = 0.006). These data suggest that the occurrence of the variants may have a direct effect on tumor development and may, in some cases, be incompatible with p53 mutations.
 ...
PMID:Two variants of the CIP1/WAF1 gene occur together and are associated with human cancer. 765 64

Cytotoxic T-lymphocytes (CTL) recognize processed peptide fragments of any endogenous protein, after these peptides are carried to the cell surface by class I major histocompatibility molecules. Thus, a tumor antigen does not have to be expressed as an intact protein on the cell surface to be recognizable by CTL. However, mutant oncogene products have not yet been shown to be targets of CD8+ CTL. Here, we generate p53-specific CD8+ CTL by immunizing BALB/c mice with spleen cells pulsed with a peptide, corresponding to a 21-amino acid sequence encompassing a point mutation (135 Cys to Tyr) in the mutant p53 gene product from a human lung carcinoma. The mutation created a new Kd class I molecule binding motif sequence, and the determinant recognized was mapped to this motif and presented by the Kd class I molecule. The wild type peptide, without the mutation, was not recognized. Importantly, the CTL killed specifically BALB/c fibroblasts transfected with the mutant p53 gene and endogenously expressing the mutant protein, but not control fibroblasts or ones transfected with a different human mutant p53 gene. Thus, endogenously synthesized mutant p53, at levels found in tumors, can render cells targets for specific CTL, and these CTL can be generated by peptide immunization. These findings point the way toward an approach to selective immunotherapy against tumors.
 ...
PMID:A mutant p53 tumor suppressor protein is a target for peptide-induced CD8+ cytotoxic T-cells. 768 15

We investigated the possibility that a proportion of children with sporadic rhabdomyosarcoma (RMS) carry constitutional mutations of the p53 tumor suppressor gene. 33 patients with sporadic RMS at two large outpatient pediatric oncology clinics submitted blood samples. Genomic DNA was extracted from peripheral blood leukocytes and PCR was used to amplify exons 2-11 of the p53 gene. Amplified genomic DNA was screened for the presence of germline p53 mutations using single-strand conformation polymorphism (SSCP) analysis. The DNA sequence of those samples that showed aberrant migration of bands on SSCP analysis was determined to identify the precise nature of the gene mutations. Patient records were reviewed to assess clinical correlates of the mutant p53 carrier state. Heterozygous constitutional mutations were detected in 3/33 patient samples screened. Two of these missense mutations are located in exon 7 and one in exon 8 of the p53 gene. The presence of mutations was not correlated with tumor histology, stage, or site. However, an association between young age at diagnosis and presence of a constitutional p53 mutation was noted: 3/13 children under the age of 3 yr at diagnosis carried mutations, whereas none of 20 children over 3 yr of age at diagnosis harbored a detectable constitutional mutation. These results in children with RMS corroborates previous findings in other clinical settings suggesting that the mutant p53 carrier state may predispose individuals to malignancy at an early age. Although this study did not assess whether the mutations were preexisting or new germline alterations, assessment of close relatives of RMS patients for cancer risk and predictive genetic testing may be indicated.
 ...
PMID:Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma. 770 67

The possibility that appropriately designed chemotherapy could act selectively against p53-defective tumor cells was explored in MCF-7 human breast cancer cells. These cells were chosen because they have normal p53 function but are representative of a tumor cell type that does not readily undergo p53-dependent apoptosis. Two sublines (MCF-7/E6 and MCF-7/mu-p53) were established in which p53 function was disrupted by transfection with either the human papillomavirus type-16 E6 gene or a dominant-negative mutant p53 gene. p53 function in MCF-7/E6 and MCF-7/mu-p53 cells was defective relative to control cells in that there were no increases in p53 or p21Waf1/Cip1 protein levels and no G1 arrest following exposure to ionizing radiation. Survival assays showed that p53 disruption sensitized MCF-7 cells to cisplatin (CDDP) but not to several other DNA-damaging agents. CDDP sensitization was not limited to MCF-7 cells since p53 disruption in human colon carcinoma RKO cells also enhanced sensitivity to CDDP. Contrary to the other DNA-damaging agents tested, CDDP-induced DNA lesions are repaired extensively by nucleotide excision, and in agreement with a defect in this process, MCF-7/E6 and MCF-7/mu-p53 cells exhibited a reduced ability to repair a CDDP-damaged chloramphenicol acetyltransferase-reporter plasmid transfected into the cells. Therefore, we attributed the increased CDDP sensitivity of MCF-7 cells with disrupted p53 to defects in G1 checkpoint control, nucleotide excision repair, or both. The G2 checkpoint inhibitor pentoxifylline exhibited synergism with CDDP in killing MCF-7/E6 cells but did not affect sensitivity of the control cells. Moreover, pentoxifylline inhibited G2 checkpoint function to a greater extent in MCF-7/E6 than in the parental cells. These results suggested that, in the absence of p53 function, cancer cells are more vulnerable to G2 checkpoint abrogators. Our results show that a combination of CDDP and pentoxifylline is capable of synergistic and preferential killing of p53-defective tumor cells that do not readily undergo apoptosis.
 ...
PMID:Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxifylline. 771 69

Proliferating cell nuclear antigen (PCNA), nuclear DNA content and mutant p53 overexpression were studied by means of image cytometry and immunohistochemistry respectively in normal mucosa (n = 10), in mild (n = 16), moderate (n = 9) and severe (n = 17) atypical lesions, as well as in squamous cell carcinomas (n = 36) of the cervix uteri. The results show that increasing histopathological atypia in the cervical mucosa was correlated to an initial increase of PCNA followed by distinct aneuploidy and p53 overexpression. The data are suggested to contribute to a better understanding of the genesis of cervical carcinoma, and to indicate that the coexistence of both distinct aneuploidy and p53 immunoreactivity can be used to decide if a cell population is neoplastic, whereas the absence of p53 overexpression does not necessarily exclude neoplasia. This diagnostic procedure can be suggested to improve early detection of intraepithelial squamous neoplasia.
 ...
PMID:The relationship between proliferating cell nuclear antigen (PCNA), nuclear DNA content and mutant p53 during genesis of cervical carcinoma. 771 54

The sensitivity of polymerase chain reaction (PCR)-based methods for the detection of DNA offers opportunities for tumor diagnosis from the small amounts of tumor-derived DNA released into body fluids. Tumor-derived DNA can be distinguished from DNA derived from non-neoplastic cells by the presence of tumor specific genomic alterations, such as mutations in the p53 gene. This case report describes the use of allele-specific PCR (A-PCR) to detect a C-->T transition in p53 codon 273 in DNA extracted from the cerebrospinal fluid (CSF) of a patient whose glioblastoma contained the same mutation. The results of this study were confirmed by a second independent A-PCR reaction that detected the corresponding G-->A transition on the opposite strand. The specificity of the A-PCR protocol was demonstrated by negative controls, including pooled human placental DNA and the patient's non-tumor DNA, and by the use of A-PCR primers to detect all four possible bases at the site of the mutation. The methodology used in this study is suitable for use as a diagnostic clinical test. Because about half of all human tumors contain p53 mutations, PCR examination of CSF for the presence of mutant p53 sequences may be useful in the diagnosis of recurrent or metastatic tumors. Patients with known carcinoma of the breast or lung might be particularly benefited by this test.
 ...
PMID:PCR-detection of tumor-derived p53 DNA in cerebrospinal fluid. 772 35

We wished to examine the role of transforming growth factor-beta (TGF-beta) in the regulation of human lymphoma cell growth. The RL cell line is an immunoglobulin M (IgM)+, IgD+ B lymphoma cell line, which does not constitutively express receptors for TGF-beta, and thus has lost the ability to respond to the inhibitory effects of TGF-beta. We demonstrate here that anti-Ig antibodies can efficiently upregulate the expression of TGF-beta receptors and promote sensitivity to growth inhibition by TGF-beta. Furthermore, because TGF-beta has been shown to function in late G1 of the cell cycle, we examined the ability of TGF-beta to modulate two tumor suppressor proteins known to be critical regulators of the G1/S transition, Rb and p53. Rb is a 105- to 110-kD phosphoprotein, which has been shown to maintain its growth suppressive function when it is found in the hypophosphorylated state. Wild-type p53 is a 53-kD phosphoprotein that appears to be important in preventing cell-cycle progression and promoting apoptosis in cells with DNA damage, whereas mutant p53 can overcome those functions. We show here that TGF-beta treatment of phorbol myristate acetate (PMA) or anti-Ig-activated RL cells results in growth inhibition through a dual effect on Rb and mutant p53. After TGF-beta treatment, we observe a predominance of Rb in the hypophosphorylated, growth suppressive form. In addition, we show a decrease in levels of mRNA and protein for mutant p53. We also show that, although these changes are sufficient to halt progression through the cell cycle, the cells do not appear to undergo extensive programmed cell death following 72 hours of TGF-beta treatment. Thus, although these lymphoma cells maintain the capacity to be negatively growth regulated by TGF-beta, the ability of TGF-beta to induce apoptosis must be independently controlled.
 ...
PMID:Anti-IgM induces transforming growth factor-beta sensitivity in a human B-lymphoma cell line: inhibition of growth is associated with a downregulation of mutant p53. 772 77

Three widely studied cell lines were used to examine the nature of the G1 arrest induced in human tumor cells by ionizing radiation and its relation to p53 status. Cell lines MCF-7 and RKO express wild-type p53, whereas HT29 expresses mutant p53. Exponentially growing cells were irradiated with 6 Gy, and the progression of G1 cells into S phase was monitored at regular intervals by flow microfluorimetric and continuous labeling autoradiographic techniques. In some experiments, cells were incubated with Colcemid prior to irradiation in order to block them in mitosis and to prevent the accumulation of cells in the second post-irradiation G1 phase. No evidence of a significant arrest at the first post-irradiation G1-S checkpoint was observed in any of the three cell lines. These results suggest that p53 function alone does not control the progression of irradiated human tumor cells from G1 into S during the first post-irradiation cell cycle. In particular, we found no evidence that radiation induced a prolonged G1 arrest in tumor cells expressing wild-type p53 as has been reported by some investigators.
 ...
PMID:Relationship between radiation-induced G1 phase arrest and p53 function in human tumor cells. 772 50


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>