Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An immunohistochemical study of snuff-induced lesions with a monoclonal antibody (DO-7) specific to p53 mutant and wildtype antioncogene product demonstrated nuclear overexpression of the mutant protein in 45.9 nuclear profiles/mm2 epithelium (SEM 10.8; n = 15) compared with only 0.18 positively stained nuclear profiles/mm2 in the control group (SEM 0.18; n = 4). Furthermore, the biopsy material was also stained with the antibody Ki-67, which has been shown to be excellent for the estimation of the growth fraction in both normal and malignant human tissues. Ki-67 stained positive in 566.1 nuclear profiles/mm2 epithelium (SEM 85.0; n = 15) in the snuff-group compared with 20.2 nuclear profiles/mm2 (SEM 4.9; n = 4) in the control group. To the best of our knowledge, this is the first study showing overexpression of p53 protein and Ki-67 in snuff-induced lesions. The results may indicate that the p53 gene is involved in the initial events leading to subsequent malignant transformation of oral mucosa exposed to snuff. Furthermore, mutations of the p53 gene have been associated with increased cellular proliferation with greater risk of perpetuation of mutations and malignant transformation.
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PMID:Assessment of p53 and Ki-67 expression in snuff-induced lesions. 890 32

p21(WAF1/CIP1) (p21) is an inhibitor of cyclin-dependent kinases recently identified as the downstream effector of wild-type p53-mediated cell cycle arrest. The gene coding for p21 may function as a negative regulator of melanoma growth, progression, and metastasis. Using immunohistochemistry and Western blotting, we investigated the expression of p21 in human melanocytic proliferations. Immunohistochemical staining was performed on 13 common acquired nevi, 12 dysplastic nevi, 23 primary malignant melanomas, and 12 metastatic melanomas. Common acquired nevi showed minimal p21 staining (1.8+/-0.3%, mean+/-SEM). The percentage of positive nuclei was slightly elevated in dysplastic nevi (8.9+/-1.7%). Both primary malignant melanoma (29+/-3%) and metastatic melanoma (33+/-5%) demonstrated a significantly increased number of p21-positive nuclei compared to benign lesions (p<0.001). p21 was strongly expressed even in actively proliferating lesions as confirmed by MIB-1 labelling, and although the majority of p21-positive cells likely represent a non-proliferating population, staining was occasionally observed in cells undergoing mitosis, suggesting abnormal function of this cell cycle inhibitor in malignant melanoma. Overexpression of p21 in metastatic melanoma compared to common acquired nevi was confirmed by Western blot analysis of human tumor samples. These findings suggest that increased p21 expression relative to benign nevi is not sufficient to control melanoma growth in vivo.
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PMID:Overexpression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) in human cutaneous malignant melanoma. 919 78

Nineteen benign [World Health Organization (WHO) grade I; MI], 21 atypical (WHO grade II; MII), and 19 anaplastic (WHO grade III; MIII) sporadic meningiomas were screened for chromosomal imbalances by comparative genomic hybridization (CGH). These data were supplemented by molecular genetic analyses of selected chromosomal regions and genes. With increasing malignancy grade, a marked accumulation of genomic aberrations was observed; i.e., the numbers (mean +/- SEM) of total alterations detected per tumor were 2.9 +/- 0.7 for MI, 9.2 +/- 1.2 for MII, and 13.3 +/- 1.9 for MIII. The most frequent alteration detected in MI was loss on 22q (58%). In MII, aberrations most commonly identified were losses on 1p (76%), 22q (71%), 14q (43%), 18q (43%), 10 (38%), and 6q (33%), as well as gains on 20q (48%), 12q (43%), 15q (43%), 1q (33%), 9q (33%), and 17q (33%). In MIII, most of these alterations were found at similar frequencies. However, an increase in losses on 6q (53%), 10 (68%), and 14q (63%) was observed. In addition, 32% of MIII demonstrated loss on 9p. Homozygous deletions in the CDKN2A gene at 9p21 were found in 4 of 16 MIII (25%). Highly amplified DNA sequences were mapped to 12q13-q15 by CGH in 1 MII. Southern blot analysis of this tumor revealed amplification of CDK4 and MDM2. By CGH, DNA sequences from 17q were found to be amplified in 1 MII and 8 MIII, involving 17q23 in all cases. Despite the high frequency of chromosomal aberrations in the MII and MIII investigated, none of these tumors showed mutations in exons 5-8 of the TP53 gene. On the basis of the most common aberrations identified in the various malignancy grades, a model for the genomic alterations associated with meningioma progression is proposed.
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PMID:Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression. 940 79

Apoptosis of vascular smooth muscle cells is critically involved in progression of atherosclerosis and may prevent intimal hyperplasia in restenosis and vascular remodeling. Nitric oxide (NO) is known to induce apoptosis, but the signaling pathways still remain unclear. We investigated p53 accumulation, protein kinase C (PKC) activation and nuclear transcription factor (NF-kappaB) binding activity as possible signaling mechanisms of NO-induced apoptosis. Apoptosis was induced dose-dependently with the NO-donors sodiumnitroprusside (SNP: 232+/-48%) and SIN-1 (241+/-90% of actinomycin D induced apoptosis; means +/- SEM, *p< or =0.05 vs. control) in HSMC. Inhibition of PKC significantly attenuated NO-induced apoptosis. Staurosporine reduced SIN-1/SNP-mediated DNA fragmentation by 55.3+/-13.8% and 38.3+/-13.9% respectively. Comparable results were obtained for calphostin C. However, NO-mediated induction of apoptosis was not preceded by p53 accumulation. SNP decreased NF-kappaB binding activity in HSMC. These results suggest that induction of apoptosis by exogenous NO in HSMC is not dependent on p53 accumulation but involves protein kinase C signaling and regulation of NF-kappaB binding activity. This opens a new therapeutical approach in preventing restenosis after angioplasty.
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PMID:Involvement of PKC and NF-kappaB in nitric oxide induced apoptosis in human coronary artery smooth muscle cells. 1168 11

The checkpoint protein p53, which is activated by DNA damage, is involved in the decision whether the cells should stop replication and proceed to repair their DNA or die by apoptosis. We evaluate the expression of p53 and the number of apoptotic cells in normal sun-exposed (face) and protected (abdomen) skin in Egyptians between 6 and 77 years of age. The degree of p53 expression in facial skin significantly increases from a score of 1.5 +/- 1.5 (mean +/- SEM) in the 1st decade to 4.8 +/- 0.3 in the 8th decade (p = 0.02), while no significant changes are detected in the protected skin (p = 0.1). Overall, the level of expression is significantly higher in sun-exposed facial skin than in abdominal skin (p = 0.007). However, p53 expression versus age is significantly higher in the facial skin of older age groups in both males (p = 0.003) and females (p = 0.02). The pattern of staining was found to be dispersed (wild-type) in the majority (97.3%) of biopsies from sun-exposed skin and in all biopsies from non-exposed skin. The expression of wild-type p53 in type IV-V skin therefore correlates with both site and age of the individual. In contrast, the number of apoptotic cells significantly decreases with advancing age in sun-exposed skin (p = 0.005). Increased age-associated expression of p53 in sun-exposed skin, but not in protected areas of skin, is found to reflect an accumulation of the wild-type protein, as judged by the staining pattern. The decrease in apoptotic cells with age may suggest the accumulation of senescent cells in the skin and their relative resistance to apoptosis. Such alteration in the proliferation/apoptosis balance could play a role in tumorigenesis.
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PMID:Expression of p53 in normal sun-exposed and protected skin (type IV-V) in different decades of age. 1273 36

Von Hippel-Lindau (VHL) gene is a tumor suppressor gene that plays a genome "gatekeeper'' role and controls several downstream effector genes. We have previously demonstrated that both in vivo and in vitro adenovirus-mediated gene transfer of tumor suppressor genes into the vascular endothelium is effective in decreasing neointimal hyperplasia and abnormal cell proliferation. The degree of apoptosis induced by these genes is critical in mediating the in vivo responses to gene therapy and the maintenance of the crucial balance between cell death and viability. Since VHL gene is known to regulate vascular endothelial growth factor (VEGF) as well as other angiogenic factors, it may exhibit a greater potential in the attenuation of vascular disorders in comparison to other tumor suppressor genes. This study focused on whether adenovirus-mediated VHL gene transfer into human vascular smooth muscle cells has an effect on cell proliferation and induction of apoptosis. Human aortic smooth muscle cells (HASMC) were grown as monolayers and transfected with varying titers of adenovirus containing the VHL cDNA (AdVHL). The negative controls were adenovirus containing green fluorescent protein (AdGFP), vector alone (AdNull), and virus-free infection medium. Adenovirus encoding wild-type p53 (Adp53) was used as positive control. Cell viability and proliferation were determined by using trypan blue exclusion and MTS-based CellTiter 96 AQ Proliferation Assay. Apoptosis was evaluated by TUNEL assay, morphologic changes, and nucleosomal DNA degradation. Following AdVHL transfection HASMCs demonstrated a dose-dependent decrease in viability as compared to negative controls (p < 0.05). AdVHL-transfected cells exhibited a decrease in their proliferative ability by 40.21 +/-1.66 (SEM)%. In cultures transfected with the positive control, Adp53, the cell viability as well as proliferation was highly reduced (p < 0.001). AdGFP and AdNull did not increase HASMC apoptosis above baseline levels. The cells exposed to adenoviruses expressing tumor suppressor genes underwent apoptosis, with Adp53 demonstrating a very high magnitude of cell death (75.27 +/-3.52 [SEM]%). AdVHL expression caused 45.36 +/-2.55 (SEM)% apoptosis in HASMC. Recombinant adenovirus-mediated VHL expression is efficacious in limiting vascular smooth muscle cell growth in vitro. Overexpression of VHL suppresses HASMC proliferation and regulates apoptosis. Further experiments are indicated to examine whether VHL may be a useful adjunct in limiting myointimal hyperplasia.
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PMID:The effect of von hippel-lindau gene transfer on human vascular smooth muscle cell proliferation and apoptosis. 1569 45

In the Western world cancer is the second leading cause of mortality, and prostate carcinoma represents in men the second most important type of cancer-causing death. We have already shown that resveratrol (200 microM) triggers in DU145, an androgen-resistant prostate cancer cell line, a necrotic-like cell death, while propolis ethanolic extract (100 microg/ml) causes an apoptotic-like cell demise. The present research is aimed to better elucidate the molecular mechanisms activated by the two micronutrients. Vinorelbine bitartrate, a drug widely used in prostate cancer therapy, was utilized as a reference drug, because it is known to induce apoptosis. The combined treatments between the micronutrients and vinorelbine have been studied to test a possible vinorelbine dose reduction, avoiding its side effects without altering its cytotoxic action. In this investigation SEM and TEM analyses were performed to examine the morphological modifications induced; our observations confirmed necrotic cell features after treatment with resveratrol, and apoptotic modifications after propolis. We also measured cell cycle progression to study a correlation with p21 and p53, two well-known cell cycle checkpoints. The levels of HSP27 and HSP70, two chaperones also exerting antioxidant/antiapoptotic functions, were been also analyzed. Our data indicate that the two micronutrients modulate cell cycle distribution, increasing p53 levels, without the induced HSPs being able to rescue DU145 from death. The results presented suggest chemotherapy based on resveratrol and propolis, alone or in combination with vinorelbine, as a potential useful tool for prostate cancer therapy; the increase in cell cycle control and the modulation of HSPs expression reinforce this suggestion.
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PMID:Resveratrol and propolis extract: an insight into the morphological and molecular changes induced in DU145 cells. 1655 47

Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors are representative agents for the chemoprevention of sporadic colorectal neoplasia. However, few reports have described the chemopreventive effects of such agents on colitis-associated tumorigenesis. To clarify whether treatment with the COX-2 inhibitor may reduce the risk of colitis-associated neoplasia, we investigated the effect of one such agent, etodolac, on tumorigenesis in the colitis-associated neoplasia model using p53-deficient mice treated with dextran sulfate sodium (DSS). The p53-/- mice were divided into four groups: i) treatment with DSS + etodolac, then after two cycles of DSS, the mice were given distilled water for 84 days. In addition, etodolac was administered three times a week at a dose of 10 mg/kg body weight throughout the experiment. ii) Treatment with two cycles of DSS only, followed by distilled water for 84 days. iii) Treatment with etodolac alone. iv) Distilled water alone was administered to the control group. The incidence of mice with neoplasia was 82.4% in the DSS + etodolac group and 100% in the DSS-alone group. No neoplasia was observed in the etodolac-alone and control groups. The mean (+/- SEM) number of total neoplasias per mouse was 1.29+/-0.2 in the DSS + etodolac group and 3.0+/-0.52 in the DSS-alone group, the inter-group difference being significant (p<0.01). There was no significant difference in the inflammation score between these two groups. These results showed that treatment with etodolac significantly reduced the occurrence of neoplasia, suggesting that this COX-2 inhibitor has chemopreventive activity against colitis-associated tumorigenesis.
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PMID:Inhibitory effects of the cyclooxygenase-2 inhibitor, etodolac, on colitis-associated tumorigenesis in p53-deficient mice treated with dextran sulfate sodium. 1820 86

Pituitary adenomas sometimes progress after surgery and can be locally invasive. Ki-67 and p53 expression are referred to as indicators of aggressive behavior in the World Health Organization Classification of Endocrine Tumors. The real value of these markers including an appropriate threshold for Ki-67 labeling index correlating with tumor progression is controversial. We identified 24 consecutive pituitary adenomas from patients who required surgery for recurrence within 5 years of their first procedure and 31 consecutive adenomas with no evidence of postsurgical progression within 5 years of first surgery. Case selection was based upon availability of complete clinical information, blocks, and slides for study. Immunohistochemistry for Ki-67 revealed that the tumors without progression had a proliferation index of 0.41% +/- 0.01% (mean +/- SEM) (n = 31) (range, 0.08%-1.2%) and the first biopsy from those tumors which progressed had a mean proliferation index of 1.45% +/- 0.09% (mean +/- SEM) (n = 24) (range, 0.1%-10.6%) (P = .01). With the use of ROC analysis, a threshold level of Ki-67 expression greater than 1.3% predicts progression with a high specificity. The group with progression had a higher proportion of nonfunctioning tumors (P < .005, chi(2)). There was no significant difference between the 2 groups with regard to invasion, suprasellar extension, size, tumor type, postoperative radiotherapy, extent of resection, sex, and age. Ki-67 labeling index was an independent predictor of progression (multivariate analysis, P < .011). p53 was positive in 12.5% of cases with surgical progression and in 9.6% of cases without progression, but the difference was not significant (P = .7; chi(2), 0.11).
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PMID:Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas. 1843 42

As mutation and dysfunction of p53 gene could induce most of human cancers, the p53 tumor suppressor gene was used to replace them and recover their normal functions in cancer cells. In this paper, biotinylated transferrin/avidin/biotinylated disulfide containing PEI bioconjugates (TABP-SS) mediated p53 gene delivery system was formed attributed to the 'avidin-biotin bridge'. Characteristics of the obtained TABP-SS and its p53 complexes were evaluated in terms of acid-base titration, agarose gel electrophoresis, SEM, particle size and zeta-potential measurements. The acid-base titration results showed that TABP-SS had good buffer capability. The results of gel electrophoresis indicated that TABP-SS could fully condensed DNA and would be degraded by reducing agent inside cells. In vitro cell viability and transfection of TABP-SS were investigated in COS7, HepG2, and HeLa cells. Among the three different cell lines, TABP-SS exhibited much lower cytotoxicity and higher transfection efficacy in HepG2 and HeLa cells due to the specific interactions between transferrin ligands and their receptors on tumor cells. Apoptotic morphology was observed using confocal microscopy, and the expression of p53 protein in transfected cells was evaluated by western blotting. All the results indicated that TABP-SS/p53 complex could be considered as a low toxic and high efficient tumor targeted gene delivery system, which has great potential for further clinical application.
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PMID:Biotinylated transferrin/avidin/biotinylated disulfide containing PEI bioconjugates mediated p53 gene delivery system for tumor targeted transfection. 2021 42


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