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)

Mutations affecting the p53 gene have been found associated with many human malignancies, but little is as yet known about multiple myeloma. We investigated p53 gene alterations in 10 human myeloma cell lines (HMCL), half of these being dependent upon exogenous interleukin 6 (IL-6) for in vitro growth, similar to freshly explanted myeloma cells. Using a polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) approach, eight of the 10 HMCL were found to bear a mutated p53 gene. All the mutations were single base substitutions with a predominance of G:C to A:T transitions. There was no apparent relation between the presence of a mutation and IL-6 requirement of the cell line. Interestingly, in two cell lines (XG-2 and XG-4) the SSCP pattern showed the presence of both the wild-type and the mutated allele and, upon reverse PCR on RNA, both alleles were found to be concomitantly expressed at the RNA level. Moreover, three freshly explanted tumor samples had the same p53 gene status (mutated versus wild type) as the HMCL that were derived from them. These results show that p53 mutations are frequent in HMCL. Although no apparent relation could be evidenced with the loss of exogenous IL-6 requirement, it may prove interesting to investigate further potential relations between the presence of a mutated p53 allele and gradual autonomy for cell growth.
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PMID:Mutations of the p53 gene in human myeloma cell lines. 137 72

The aberrant overexpression of interleukin 6 (IL-6) is implicated as an autocrine mechanism in the enhanced proliferation of the neoplastic cell elements in various B- and T-cell malignancies and in some carcinomas and sarcomas; many of these neoplasms have been shown to be associated with a mutated p53 gene. The possibility that wild-type (wt) p53, a nuclear tumor-suppressor protein, but not its transforming mutants might serve to repress IL-6 gene expression was investigated in HeLa cells. We transiently cotransfected these cells with constitutive cytomegalovirus (CMV) enhancer/promoter expression plasmids overproducing wt or mutant human or murine p53 and with appropriate chloramphenicol acetyltransferase (CAT) reporter plasmids containing the promoter elements of human IL-6, c-fos, or beta-actin genes or of porcine major histocompatibility complex (MHC) class I gene in pN-38 to evaluate the effect of the various p53 species on these promoters. Murine and human wt p53 derived from pCMVNc9 and pC53-SN3, respectively, strongly repressed the IL-6 (promoter position -225 to +13), c-fos (-711 to +42), beta-actin (-3400 to +912), and MHC (-528 to -38) promoters in serum-induced HeLa cells; additionally, IL-6 promoter/CAT transcription unit constructs induced by IL-1, phorbol ester, or pseudorabies virus were also repressed by wt human and murine p53. The murine transforming mutant p53 (pCMVc5) was less active in repressing the IL-6, c-fos, beta-actin, and MHC promoter constructs. The human p53 mutant derived from pC53-SCX3 was also less active than the wt protein in repressing the IL-6, c-fos, beta-actin, and MHC promoters, except that serum-induced IL-6/CAT expression was equally repressed by both human wt and mutant p53. In similar transient transfection experiments in HeLa cells, overexpression of the wt human retinoblastoma susceptibility gene product, RB, was found to repress the serum-induced IL-6 (-225 to +13), c-fos (-711 to +42), and beta-actin (-3400 to +912) promoters but not the PRV-induced IL-6 (-110 to +13) or the serum-induced MHC (-528 to -38) promoters. These observations identify transcriptional repression as a property of p53 and suggest that p53 and RB may be involved as transcriptional repressors in modulating IL-6 gene expression during cellular differentiation and oncogenesis.
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PMID:Repression of the interleukin 6 gene promoter by p53 and the retinoblastoma susceptibility gene product. 165 55

Induction of differentiation in M1 myeloid leukemic cells by the hematopoietic cytokines interleukin 6 and granulocyte-colony stimulating factor, or by the glucocorticoid dexamethasone, was associated with down-regulation of the apoptosis inhibiting gene bcl-2. The cytokine treated leukemic cells showed an increased sensitivity to induction of apoptotic cell death by the cancer chemotherapy compounds Adriamycin and cytosine arabinoside and by heat shock and cycloheximide. Dibutyryl cyclic AMP neither induced differentiation nor down-regulated bcl-2 expression, but it sensitized the cells to induction of apoptosis by some of these agents. Although dexamethasone induced differentiation and down-regulated bcl-2 expression, it did not sensitize the cells to induction of apoptosis and inhibited the apoptosis sensitizing effect of the cytokines and dibutyryl cyclic AMP. Dexamethasone did not inhibit induction of apoptosis by wild-type p53 or viability factor withdrawal. The apoptosis sensitizing effect of the cytokines and dibutyryl cyclic AMP was reversible upon their withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Control of sensitivity to induction of apoptosis in myeloid leukemic cells by differentiation and bcl-2 dependent and independent pathways. 751 74

Hormonal treatment of advanced prostatic cancer patients generally results in an initially beneficial response, but the treated patients develop hormonally resistant disease in which no curative therapy is currently available. Recent studies have revealed that interleukin 6 (IL-6) is a growth factor for myeloma, renal cell carcinoma, and certain T-cell lymphomas. Further, IL-6 has been shown to block apoptosis induced by p53, transforming growth factor beta, and certain cancer chemotherapeutic compounds. The objective of the present study was to determine whether IL-6 is a growth factor for two human prostate cancer lines and whether it protects the tumor cells from drug-induced cell death. Two hormone-independent prostate cell lines were used in this study, namely PC-3 and DU145, and these have been shown to be relatively resistant to cis-diamminedichloroplatinum (CDDP), etoposide (VP-16), and adriamycin (ADR). Both cell lines express IL-6 mRNA and secrete IL-6 constitutively. The addition of anti-IL-6 antiserum to the cell lines resulted in a significant inhibition of cell growth up to day 2, and when additional antibody was added at day 2 the inhibition persisted for 4 days. The coaddition of anti-IL-6 antiserum and CDDP or VP-16 resulted in synergy in cytotoxicity in both cell lines, whereas the combination of antibody and ADR or suramin resulted only in additive effects. Sequential treatment revealed that anti-IL-6 antibody was required to achieve synergy, whereas either sequence of pretreatment resulted in synergy with anti-IL-6 and CDDP but not with VP-16. CDDP treatment of tumor cells down-regulated IL-6 mRNA expression and IL-6 secretion. The present findings demonstrate that IL-6 is an autocrine/paracrine growth factor for DU145 and PC-3 prostate lines. Additionally, the secretion of this cytokine protects the tumor cells against the cytotoxic effect of CDDP and VP-16 and its neutralization sensitizes the cells to cytotoxicity. Overall, the studies suggest that agents that can down-regulate or inhibit protective factors in tumors may overcome drug resistance.
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PMID:Endogenous interleukin 6 is a resistance factor for cis-diamminedichloroplatinum and etoposide-mediated cytotoxicity of human prostate carcinoma cell lines. 755 41

We have studied the effects of food restriction (FR) and substitution of fish oil (FO; omega 3) for corn oil (CO; omega 6) on breast tumor incidence and survival in mouse mammary tumor virus/v-Ha-ras transgenic (Onco) mice. The diets were as follows: group 1, 5% (wt/wt) CO fed ad libitum (AL); group 2, 5% CO, restricted calories (40% fewer calories than AL; FR); group 3, 20% CO fed AL; and group 4, 20% FO fed AL. After 3 years, 40% of FR Onco (group 2) mice were alive, whereas there were no survivors in the other three groups. Similarly, tumor incidence was reduced to 27% (5 out of 18) in FR animals (group 2), whereas it was 83% (11 out of 13) in group 1 mice, 89% (16 out of 18) in group 3 mice, and 71% (10 out of 14) in group 4 mice. These protective effects of FR on survival and tumor incidence were paralleled by higher expression of the tumor suppressor gene p53 (wild type) and free-radical scavenging enzymes (catalase and superoxide dismutase) in breast tumors. Immunoblotting showed less ras gene product, p21, and increased p53 levels in the tumors of FR mice. In addition, FR decreased RNA levels of c-erbB-2, interleukin 6, and the transgene v-Ha-ras in tumors. In contrast, analysis of hepatic mRNA from tumor-bearing FR mice revealed higher expression of catalase, glutathione peroxidase, and superoxide dismutase. Survival and tumor incidence were not influenced significantly by dietary supplementation with FO in place of CO. Taken together, our studies suggest that moderate restriction of energy intake significantly inhibited the development of mammary tumors and altered expression of cytokines, oncogenes, and free-radical scavenging enzymes.
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PMID:Dietary lipids and calorie restriction affect mammary tumor incidence and gene expression in mouse mammary tumor virus/v-Ha-ras transgenic mice. 760 20

The biologic behavior of invasive pituitary adenomas is poorly understood and appears to be intermediate between intrasellar adenomas and pituitary carcinoma. Utilizing immunohistochemistry on tissue sections, we examined 10 invasive pituitary adenomas involving the sphenoid sinus with a panel of cellular and molecular markers and compared the results with 10 noninvasive pituitary adenomas and five normal pituitary glands. The panel included Ki-67 and PCNA (proliferation cell nuclear antigen), cell proliferation indicators; interleukin 6 (IL-6), a multifunctional cytokine; heat shock protein 27 (HSP 27), a stress response protein; and p53, a tumor suppressor gene product. We found strong expression of IL-6 in normal pituitary glands, 20% of noninvasive and 50% of invasive adenomas. HSP 27 was absent in normal glands and present in 10% of noninvasive and 50% of invasive adenomas. The Ki-67 and PCNA proliferation index was above normal but was essentially the same in the two groups. p53 was not detected in any specimens. We propose that both IL-6 and HSP 27 may be markers of biologic aggression in pituitary adenomas.
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PMID:Biologic markers of invasive pituitary adenomas involving the sphenoid sinus. 777 77

Fanconi anemia belongs to a group of human genetic diseases characterized by chromosomal instability, sensitivity to genotoxic agents associated to impaired processing of DNA lesions, cell cycle anomalies and cancer predisposition. We recently added to this list of distinctive features reduced production of interleukin 6 and overproduction of tumor necrosis factor alpha. Since growth factor deprivation, TNF alpha treatment or DNA damage can trigger apoptosis, we monitored the apoptotic response of FA cell lines. We show here that, although the spontaneous rate of apoptosis is slightly more elevated in FA than in normal cell cultures, the apoptosis induced by gamma-irradiation is drastically reduced in FA. Since the induction of apoptosis by radiation is a p53-dependent mechanism, the induction of this protein in FA cells was also examined. We found that the p53 protein is not radio-induced in FA cells belonging to the two genetic complementation groups examined (C and D), in contrast to normal cells. Moreover, the same impairment in p53 induction is observed after exposure to mitomycin C, a chemical agent for which FA cells demonstrate a specific cellular and chromosomal hypersensitivity, as well as after u.v.-B irradiation, an agent known to cause oxidative stress. These observations are in line with recent reports showing that at least certain cell lines from other chromosome breakage syndromes, such as ataxia telangiectasia and Bloom syndrome, may be also defective for radiation-induced increase of p53 protein. As the p53 tumor suppressor gene encodes a transcriptional activator whose targets include genes that regulate genomic stability, cellular response to DNA damage and cell cycle progression, we suggest that altered expression of p53 may be relevant to the FA phenotype.
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PMID:p53-dependent pathway of radio-induced apoptosis is altered in Fanconi anemia. 782 83

Fallopian tube carcinoma is a lethal gynecologic malignancy. Etiologic factors are unknown. No experimental data on molecular alterations exist so far. For an in vitro model, we established the permanent human tubal carcinoma cell line FT-MZ-1. The median doubling time was 14 days with 24.2% in S phase. A point missense mutation of the p53 tumor suppressor gene resulting in the His175 mutant was identified. Aberrant p53 protein accumulated in nucleus and cytoplasm. FT-MZ-1 substantially secreted interleukin 6 (Il-6) coinciding with the inactivation of p53 as a transrepressor on the Il-6 gene promoter.
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PMID:p53 mutant His175 identified in a newly established fallopian tube carcinoma cell line secreting interleukin 6. 792 16

Mammary epithelial cells (MECs) were isolated and cultured from mammary glands of healthy women undergoing reduction mammoplasty. Normal MECs were infected with the transforming hybrid virus adeno-5/SV40. Two transformed epithelial cell lines, M1 and M2, were obtained, characterised phenotypically and studied for the production of and the response to cytokines and growth regulators. In both cell lines, expression of the SV40 large T antigen was associated with loss of interleukin 6 (IL-6) production and responsiveness as well as with down-regulation of IL-8 and transforming growth factor (TGF)-alpha production. Both M1 and M2 cell lines were capable of forming colonies in semisolid media, but upon injection into severe combined immunodeficient (SCID) mice only M2 cells were tumorigenic. DNA synthesis in M1 cells was partially inhibited by serum or TNF-alpha and weakly stimulated by hydrocortisone (HC) and IL-8. In contrast, M2 cells were totally unresponsive to a variety of growth regulators. Both lines overexpressed the p53 protein at levels about 20-fold higher than those observed in primary MEC cultures, but no mutations of the p53 gene could be detected. The date confirm the view that the expression in human mammary cells of different oncogenes - including the SV40 T antigen - is frequently associated with alterations of cytokine production and responsiveness.
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PMID:Defective interleukin six expression and responsiveness in human mammary cells transformed by an adeno 5/SV40 hybrid virus. 864 79

Apoptosis induced by wild-type p53 or cytotoxic compounds in myeloid leukemic cells can be inhibited by the cytokines interleukin 6, interleukin 3, granulocyte-macrophage colony-stimulating factor, and interferon gamma and by antioxidants. The antioxidants and cytokines showed a cooperative protective effect against induction of apoptosis. Cells with a higher intrinsic level of peroxide production showed a higher sensitivity to induction of apoptosis and required a higher cytokine concentration to inhibit apoptosis. Decreasing the intrinsic oxidative stress in cells by antioxidants thus inhibited apoptosis, whereas increasing this intrinsic stress by adding H2O2 enhanced apoptosis. Induction of apoptosis by wild-type p53 was not preceded by increased peroxide production or lipid peroxidation and the protective effect of cytokines was not associated with a decrease in these properties. The results indicate that the intrinsic degree of oxidative stress can regulate cell susceptibility to wild-type p53-dependent and p53-independent induction of apoptosis and the ability of cytokines to protect cells against apoptosis.
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PMID:Cellular oxidative stress and the control of apoptosis by wild-type p53, cytotoxic compounds, and cytokines. 879 72


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