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)

Lung cancer is the leading cause of cancer death in the United States. Small cell lung cancer (SCLC) accounts for 20% to 25% of all bronchogenic carcinoma and is associated with the poorest 5-year survival of all histologic types. SCLC differs in its etiologic, pathologic, biologic, and clinical features from non-SCLC, and these differences have translated to distinct approaches to its prevention and treatment. Compared with other histologic types of lung cancer, exposures to tobacco smoke, ionizing radiation, and chloromethyl ethers pose a substantially greater risk for development of SCLC. The histologic classification of SCLC has been revised to include three categories: (1) small cell carcinoma, (2) mixed small cell/large cell, and (3) combined small cell carcinoma. Ultrastructurally, SCLC displays a number of neuroendocrine features in common with pulmonary neuroendocrine cells, including dense core vesicles or neurosecretory granules. These dense core vesicles are associated with a variety of secretory products, cell surface antigens, and enzymes. The biology of SCLC is complex. The activation of a number of dominant proto-oncogenes and the inactivation of tumor suppressor genes in SCLC have been described. Dominant proto-oncogenes that have been found to be amplified or overexpressed in SCLC include the myc family, c-myb, c-kit, c-jun, and c-src. Altered expression of two tumor suppressor genes in SCLC, p53 and the retinoblastoma gene product, has been demonstrated. Cytogenetic and molecular evidence for chromosomal loss of 3p, 5q, 9p, 11p, 13q, and 17p in SCLC has intensified the search for other tumor suppressor genes with potential import in this malignancy. Bombesin/gastrin-releasing peptide, insulin-like growth factor I, and transferrin have been identified as autocrine growth factors in SCLC, with a number of other peptides under active investigation. Several mechanisms of drug resistance in SCLC have been described, including gene amplification, the recently described overexpression of multi-drug resistance-related protein (MRP), and the expression of P-glycoprotein. The classic SCLC staging system has been supplanted by a revised TNM staging system where limited disease and extensive disease are equivalent to the TNM stages I through III and stage IV, respectively. Therapeutically, recent strategies have attained small improvements in survival but significant reductions in the toxicities of chemotherapeutic regimens. Presently, the overall 5-year survival for SCLC is 5% to 10%, with limited disease associated with a significantly higher survival rate.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Small cell lung cancer: etiology, biology, clinical features, staging, and treatment. 839 98

The antioxidant alpha-tocopherol and the weaker antioxidant and prooxidant chemopreventative, beta-carotene have been shown to inhibit tumor cell growth in vivo and in vitro. In some epidemiologic studies their serum levels were demonstrated to be inversely related to the incidence of malignant tumor. We hypothesized two basic pathways triggered by antioxidants and prooxidants, which resulted in the control of tumor cell growth. These included changes in phosphorylation and ultimately transcription. Specifically, the prooxidant beta-carotene treatment produced an oxidative stress resulting in the selective induction of heat shock proteins (hsps). These proteins and other proteins that were possibly oxidized were associated with the increased expression of cyclins (A and D) and increased cdc2 kinase expression. An increase in expression of phosphoproteins, such as p53 (tumor suppressor form) was also discerned. The level of expression for the transcription factor c-fos was reduced. Growth factors that contribute to tumor cell growth were also reduced. Increased DNA fragmentation, depression of proliferation and intracellular calcium levels, the accumulation of tumor cells in G0-->G1, and morphologic changes, were consistent with programmed cell death. Antioxidants such as alpha-tocopherol bound to membrane-associated proteins could inhibit the development of peroxidation products (hydroxyl radicals (.OH)), which attack proteins and modify their function and promote their degradation. Some kinases such as, cdc2 may be increased in activity, which would explain the observed increased expression of tumor suppressor p53, the accumulation of the tumor cells in G1 of the cell cycle and the inhibition of tumor cell proliferation. A reduction in oxidant radicals could also reduce transcription factor products, such as c-myb. Indirectly this result may occur through changes in nuclear translocation (signaling) NF-AT or the Rel-related family of transcription factors, including NF-kB (p50 or p65) or inhibition of immunophilin-calmodulin activity. Although the data remains fragmentary there are common points for control for tumor cell growth resulting from the effects of alpha-tocopherol or beta-carotene treatment. These changes involve phosphorylation and protein expression. Ultimately there is a reduction of important transcription factor protein products, a reduction in response to growth factors, and suppression of cell proliferation, resulting in increased control of the cell cycle.
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PMID:Molecular and biochemical reprogramming of oncogenesis through the activity of prooxidants and antioxidants. 851 52

c-myb, a protooncogene prevalently expressed in the hematopoietic tissue, is a transcription factor that contains a DNA-binding domain and an acidic domain and is able to transactivate specific viral and cellular genes. In this report, we show that c-myb can stimulate apoptosis in both the murine promyelocytic 32D and the human osteosarcoma SAOS2 cell lines when coexpressed with p53. Apoptosis is accompanied by increased transactivation of the cell death-associated BAX gene. This effect is c-myb specific, because B-myb is not able to cooperate with p53 in the induction of BAX transcription and apoptosis. Immunoprecipitation studies and gel shift analysis indicate that c-myb does not directly interact with the BAX promoter or the p53 protein but, rather, cooperates through an indirect mechanism. Consistent with the existence of a functional link between c-myb and p53, we also observed that c-myb represses p53-induced activation of the WAF-1 promoter and induces proliferation of SAOS2 cells growth arrested by p53. These results might contribute to the elucidation of the mechanisms underlying p53-dependent pathways of oncogene-induced apoptosis and provide a further example of DNA-binding independent myb activity.
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PMID:Apoptotic response to oncogenic stimuli: cooperative and antagonistic interactions between c-myb and the growth suppressor p53. 861 38

Protooncogenes are cell cycle-related genes that are involved in cell growth of proliferation. Alterations in the level of expression of these genes, or expression of aberrant gene productions, have been observed in tumors and precancerous conditions. To determine if expression of these genes is altered in patients with inflammatory bowel disease (IBD) --who are at risk for development of colon cancer--we assayed transcripts of 15 protooncogenes in colonic epithelial cells of IBD patients and controls. Nine of these genes (H-ras, c-myc, c-fos, c-jun, junB, N-myc, c-abl, c-yes, and p53) were expressed in epithelial cells, whereas two (RB1 and N-ras) were not. expression of four other genes (c-src, K-ras, c-raf, and c-myb) was observed, but the intensity of these bands was too low for densitometric analysis. The steady-state levels of transcripts of H-ras and five nuclear protooncogenes (c-myc, c-fos, c-jun, junB, and N-myc) were lower in epithelial cells from involved or uninvolved IBD samples than in normal epithelial cells from either sporadic colon cancer or diverticulitis patients. The level of c-fos mRNA was two- to threefold higher in involved than in uninvolved areas of the colons of two ulcerative colitis (UC) patients, but not in one Crohn's disease (CD) patient. Message abundance of c-abl transcripts was two- to threefold lower in UC epithelial cells than in either the CD or control samples. The steady-state level of c-yes-encoded mRNA was considerably higher in IBD patients resected for colon cancer than in patients resected for active chronic IBD or in controls. The level of p53 message was constant in these samples. Increased levels of c-fos mRNA in involved UC relative to uninvolved UC may be related to the disease process. Decreased expression of c-abl transcript in UC may be a diagnostic marker for UC and may be related to the rate of cell turnover in these diseases. Enhanced expression of c-yes in IBD patients with tumors compared to active chronic IBD and controls suggests that expression of this gene may be a marker for development of colon cancer in IBD.
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PMID:Expression of protooncogene-encoded mRNA by colonic epithelial cells in inflammatory bowel disease. 867 85

In the 1970s a considerable amount of work was carried out in an attempt to identify an anti-tumor serological response in cancer patients. These analyses have not been very informative due to the complexity and heterogeneity of the response. More recently, the availability of recombinant molecules, synthetic peptides and analytic and semi-quantitative assays has enabled a better dissection of humoral immunity. Antibodies against intracellular antigens (c-myb, c-myc, p53 and p21 ras) have been found in a significant, albeit varying, proportion of patients bearing various tumors. Association with a poor prognosis is documented for anti-p53 antibodies in breast carcinoma patients. A number of cell surface antigens, including mucins, oncoproteins and carbohydrate antigens have been found to elicit a humoral immune response and, in some instances, circulating immune complexes were observed. A protective role for or, on the other hand, masking effects of such antibodies is still controversial. An indication that a serological response can be beneficial comes from vaccination studies. A significant association between the development of an anti-tumor antigen antibody response and prolonged survival was observed following vaccination of melanoma patients with GM2 or anti-idiotypic antibodies which molecularly mimic tumor-associated antigens. It is to be hoped that in the near future the numerous ongoing immunization trials and prognostic studies demonstrate whether antibody response can exert a protective role in vivo.
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PMID:1975-1995 revised anti-cancer serological response: biological significance and clinical implications. 874 Jul 84

We demonstrated that tumor necrosis factor-alpha (TNF-alpha) rapidly and markedly enhances p21 gene and protein expression prior to monocytic differentiation and apoptosis in p53-null HL-60 cells. TNF-alpha induced early small and delayed large peaks of apoptosis at 6 and 48 h of incubation, respectively. At 24 h of incubation, apparent monocytic differentiation of the cells was noted. Down-regulation of c-myc and c-myb and G0/G1 arrest were observed at 6-12 and 36 h, respectively. Actinomycin D markedly inhibited TNF-alpha-induced p21 mRNA expression, suggesting that the p21 gene is induced at the transcriptional level. We confirmed that TNF-alpha induces p53-independent apoptosis in HL-60 cells, which accompanies monocytic differentiation.
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PMID:p53-independent induction of p21 (WAF1/CIP1) during differentiation of HL-60 cells by tumor necrosis factor alpha. 899 Jun 24

Mining and mineral processing are important industries in the United States. A large number of workers are potentially exposed to silica during mining and to glass fibers during manufacturing. There is a concern regarding lung cancer risk among workers exposed to silica and glass fibers. Our previous studies showed that both glass fibers and silica induced transformation of BALB/c-3T3 cells. In order to explore the relationship between silica and glass fiber-induced cell transformation and oncoprotein expression, the protein products of seven proto-oncogenes (c-K-ras, c-H-ras, c-sis, c-myc, c-myb, c-erb B1 and c-jun) and one tumor suppressor gene (p53) were examined in BALB/c-3T3 cells transformed by glass fibers or silica using immunoblotting with specific monoclonal or polyclonal antibodies. The results showed that all transformants, including eight induced by glass fibers and eight by silica (Min-U-Sil 5), were positive for c-jun protein expression; the level of c-jun protein was elevated 8-21-fold in these transformants. Other protooncogene proteins in transformed cells were either not detectable or not different from non-transformed cells. These results suggest that the overexpression of c-jun is common in BALB/c-3T3 transformed cells induced by glass fibers or silica. It seems, therefore, that the expression of c-jun may play an important role in the transformation process.
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PMID:Selective hyperexpression of c-jun oncoprotein by glass fiber- and silica-transformed BALB/c-3T3 cells. 902 70

L1210 cell lines selected for resistance to deoxyadenosine exhibit altered steady-state levels of the mRNA for the early response genes and p53. In the deoxyadenosine-resistant cell lines (Y8 and ED2), the levels of the mRNAs for p53 and c-jun were markedly decreased while the steady-state levels for mRNAs for c-myc, c-fos and jun B were elevated in the Y-8 and ED2 cell lines. The levels of the mRNAs for PCNA and c-myb were the same in the wild type and mutant cell lines. The levels of the mRNAs for krox-24 were extremely low in the wild type and mutant cell lines. Cycloheximide (CHX) treatment of the cells resulted in the increase in the mRNA levels for c-jun, jun B, krox 24 and p53 in the Y-8 and ED2 cell lines. The time courses and the extents of the increases in the mRNA levels following CHX treatment were not the same for all of these mRNAs. The level of p53 RNA increased with no lag following CHX treatment while the levels of the mRNAs for c-myc, c-jun and krox-24 increased after a one-hour lag period. The level of the mRNA for p53 and c-myc increased 20- and 7-fold, respectively while the mRNA level for knox-24 increased 80-fold following CHX treatment. The Y8 and ED2 cell lines that lack steady-state levels of p53 show decreased sensitivity to cisplatin and increased frequency of gene amplification as measured by PALA resistance in a manner similar to other cell lines lacking p53. On the other hand, the ED2 and Y8 cell lines do not show a G1-block in response to PALA treatment. The cell lines appear to offer an experimental system in which to study the interactions between/among these early response genes and the p53-dependent and independent pathways.
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PMID:Deoxyadenosine-resistant mouse leukemia L1210 cell lines with alterations in early response genes and p53. 904 10

The continued progress in our understanding of the biology of neoplasia and in the identification, cloning, and sequencing of genes critical to tumor cell function permits the exploitation of this information to develop specific agents that may directly modulate the function of these genes or their protein products. Antisense oligonucleotides are being investigated as a potential therapeutic modality that takes direct advantage of molecular sequencing. The antisense approach uses short oligonucleotides designed to hybridize to a target mRNA transcript through Watson-Crick base pairing. The formation of this oligonucleotide: RNA heteroduplex results in mRNA inactivation and consequent inhibition of synthesis of the protein product. A fundamental attraction of the antisense approach is that this method potentially may be applied to any gene product, in theory, for the treatment of malignant and non-malignant diseases. However, this simple and attractive model has proven to be much more complex in practice. A number of important challenges in the preclinical development of antisense oligonucleotides have been identified, including stability, sequence length, cellular uptake, target sequence selection, appropriate negative controls, oligonucleotide: protein interactions, and cost of manufacture. Although the biological activity of an oligonucleotide against its molecular target is theoretically sequence-dependent, the animal pharmacokinetics and toxicology of phosphorothioate analogues directed against vastly disparate gene products appear relatively non-sequence-specific. In oncology, a number of clinical trials have been initiated with antisense oligonucleotides directed against molecular targets including: p53; bcl-2; raf kinase; protein kinase C-alpha; c-myb. The experience gained from these early clinical trials will be applicable to the next generation of antisense agents in development. These may include molecules with novel backbones or other structural modifications, chimeric oligonucleotides, or peptide nucleic acids. Continued progress in this arena will require that many of the preclinical challenges confronting antisense development are satisfactory resolved.
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PMID:Antisense oligonucleotides as therapeutics for malignant diseases. 912 89

Leukemia inhibitory factor (LIF) affects the growth of carcinoma cells, and we thus analyzed its underlying mechanisms. Carcinoma cells constitutively express LIF mRNA, and 23 lines (92.0%) and all (100%) of 25 lines express LIF receptor mRNAs of LIFRbeta and gp130, respectively. Exogenous addition of LIF promoted significant cell proliferation in 4 lines (MCF-7, ZR-75-1, Hs-700T and Panc-1) and suppressed cell growth in 3 lines (AZ-521, GBK-1 and HT-29). LIF significantly induced an immediate early response of genes c-fos and junB 3 hr after stimulation, but not of c-jun during the process of proliferation of MCF-7 and Hs-700T cells, with maximum levels at 30-60 min. The cell-cycle-related gene cyclin E was also induced in MCF-7 and Hs-700T cells, whereas cyclinA, cdk2, c-myc, c-myb and p53 mRNAs were not induced. On the other hand, LIF inhibited growth and increased the rate of cell death of AZ-521 and GBK-1 cells. LIF increased the number of TUNEL-positive cells in AZ-521 cells and DNA fragmentation in AZ-521 and GBK-1 cells. LIF induced apoptosis related genes c-myc and ICE during suppression of cell growth, but p53, p21, c-fos, cyclin A and cyclin E were not induced. Our results suggest that LIF is linked to cell proliferation and apoptosis in some human carcinoma cell lines. It is considered that this is related to differences in signal transduction and induction of oncogenes.
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PMID:Leukemia inhibitory factor induces apoptosis and proliferation of human carcinoma cells through different oncogene pathways. 925 11


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