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)

Using monoclonal antibodies, we have identified a series of tumor-associated antigens selectively expressed on tumor subtypes with distinct clinical behaviours. The mucinous antigen M344 and the gp200 surface antigen 19A211 are preferentially expressed on papillary superficial tumors and carcinoma in situ lesions of the bladder. The combination of these two antigenic markers in immunocytology and flow cytometry studies of exfoliated cells has improved the sensitivity of detection for bladder tumors. Moreover, the detection of M344- and 19A211-positive exfoliated cells from previously treated but currently tumor-free patients appears to be predictive of tumor recurrence on follow-up. These results, as well as results of bladder mapping studies in tumor patients, suggest that these antigenic changes occur in a premalignant stage and may provide tools to monitor the efficacy of chemopreventive measures. Other markers, such as the surface antigen T138 and the soluble molecules autocrine motility factor (AMF) and tumor collagenase stimulating factor (TCSF), are produced by primary or recurrent tumors with a higher metastatic potential. They may be useful in identifying high risk patients for distant failure. The highly restricted antigen 19A211 is also expressed on cervix condylomas and carcinoma. This observation led us to investigate a possible viral etiology of some bladder cancers. Using PCR techniques, we detected the presence of human papillomavirus (HPV) 16 DNA sequences in a significant proportion of bladder tumors. HPV positivity was inversely correlated with the presence of p53 mutations in exons 5-9 of the same tumors as measured by PCR-SSCP technique. This combination of markers may provide a basis for chemoprevention strategies targeted to distinct etiological events.
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PMID:Strategies of chemoprevention based on antigenic and molecular markers of early and premalignant lesions of the bladder. 130 95

Human aortic endothelial cells, isolated at autopsy from a 52-year-old male dying from lung cancer, were treated with simian virus 40 (SV40). One colony was isolated from the infected endothelial cell culture 4 weeks after infection. The cells expressed SV40 large T antigen and p53 protein (p53) in their nuclei but lacted the characteristics of a transformed phenotype. The cells grew well in a monolayer over the 97th passage and exhibited Factor VIII-related antigen, Ulex europaeus 1 agglutinin (UEA-1) as endothelial cell markers, and a well-developed fibronectin network. The amount of prostacyclin synthesized by the cells was less than the amount synthesized by normal aortic or umbilical cord vein endothelial cells. The cells produced relatively large amounts of procollagenase, and 12-o-tetradecanoyl-phorbol-13-acetate (TPA) augmented the ability of the cells to produce this enzyme. These immortalized human aortic endothelial cells, which have some characteristics of normal endothelial cells and, like capillary endothelial cells, have the ability to produce collagenase, will probably prove useful for studies of atherosclerosis and angiogenesis.
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PMID:Collagenase production by immortalized human aortic endothelial cells infected with simian virus 40. 167 13

Smooth muscle cells in the thickened intima of the aorta also expressed sis, mye, and c-fos, in addition to collagen types I, III, IV and type V. In the cultures of smooth muscle cells isolated from human aorta, collagen I, III and gelatinase were produced without any other special conditions for the culture. In the presence of PDGF, collagen type V and collagenase production was detected in the culture. Oncogene expression was not detected in the cultured cells when tested by the indirect immunofluorescence technique. Immortalized smooth muscle cells with SV 40 expressed myc, SV 40 large T antigen, and p53 without inhibition of collagen and collagenolytic enzymes production.
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PMID:[Expression of oncogenes by smooth muscle cells in atherosclerotic lesions]. 215 35

Rat embryo fibroblasts (REFs) are inefficiently transformed by the T24-ras oncogene. A contributing factor to cellular resistance to transformation is the limited tolerance to p21-ras oncoprotein expression. Here we present data suggesting that long-term glucocorticoid treatment of ras oncogene-transfected REFs results in increased tolerance to p21-ras oncoproteins, leading to expression of the transformed phenotype. Stably transformed cell lines that expressed high levels of H-ras and could be maintained in the absence of hormone were isolated. In three out of four lines studied, the AP-1-dependent collagenase gene was expressed at a low level. In one of these lines, low collagenase expression was paralleled by lack of c-jun mRNA. Immunochemical analysis revealed that progression to hormone independence was not paralleled by mutations in the p53 gene. We propose that a decreased expression of AP-1-driven genes may result in increased tolerance to p21-ras oncoprotein.
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PMID:Lack of c-jun expression in a transformed cell line isolated by glucocorticoid promotion of ras-transfected rat embryo fibroblasts. 847 51

Ultraviolet radiation may be divided into the non-solar UVC region, the solar UVB (290-320 nm) region which is strongly absorbed by nucleic acids, and the solar UVA (320-380 nm) region which is less strongly absorbed by nucleic acids and proteins but causes a variety of oxidative events. As a consequence of these different properties, UVC/UVB radiations induce an array of stress proteins quite distinct from those induced by UVA radiations. Although many studies with UVC and UVB radiations involve lethal doses, it is clear that these radiations have the property of mimicking growth factor responses and stimulate various signal transduction pathways that lead to gene activation including transcriptional activation of the jun and fos proto-oncogenes. Furthermore, UVB irradiation of skin, at physiologically relevant doses can increase the levels of various stress proteins including ornithine decarboxylase, various cytokines, the p53 tumor suppressor protein and to a limited extent, nuclear oncogene products. Non-cytoxic exposures of UVA radiation can lead to the up-regulation of several genes including collagenase, heme oxygenase 1, a specific protein phosphatase (CL 100) and phospholipases. At least for heme oxygenase 1, there is evidence that the alteration may be involved in a pathway of defense against oxidative stress. However, much information is lacking in the quest to build up a complete picture of the physiological and pathological significance of the many UV inducible stress responses reported.
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PMID:UV activation of mammalian stress proteins. 885 79

We previously reported that induced activator protein-1 (AP-1) transcriptional activity appears to be required for tumor promoter-induced transformation in mouse epidermal JB6 cells. To extend this investigation to a keratinocyte culture model and a transgenic mouse model, we constructed K14TAM67, a keratin 14 promoter-controlled version of the dominant negative jun mutant to directly block AP-1 activity and possibly indirectly block NF kappa B activity in basal squamous epithelia. This study was directed at characterizing TAM67 expression and biological activity in the mouse cell line 308, a keratinocyte model for studying carcinogenesis. Cotransfection of K14TAM67 with luciferase plasmid reporter DNAs produced inhibition of basal and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced AP-1 and NF kappa B activity but had no effect on p53-dependent transcriptional activity. In an in vitro invasion assay, stable expression of TAM67 in 308 cells blocked TPA-induced Matrigel invasion. This suggests that blocking TPA-induced AP-1- or NF kappa B-regulated gene expression by TAM67 inhibits TPA-induced progression. Recombinant tissue inhibitor of metalloproteinase 1 reduced TPA-induced in vitro invasion, thus implicating metalloproteinases at least in part in the transcription factor-dependent process. Analysis of mRNA levels for members of the matrix metalloproteinase (MMP) family, however, revealed that the expression of any single MMP family member did not correlate with regulation of AP-1 or NF kappa B activity. However, the combination of substantial levels of mRNA for stromelysin-1, stromelysin-2, collagenase, membrane type 1 MMP, and gelatinase A occurred only in TPA-treated cells in the absence of TAM67. These results suggest that the action of the dominant negative jun mutant on AP-1 and NF kappa B gene regulation results in complex alterations in the levels of downstream effector genes, such as the metalloproteinases, that effect TPA-induced cellular invasion.
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PMID:A dominant negative mutant of jun blocking 12-O-tetradecanoylphorbol-13-acetate-induced invasion in mouse keratinocytes. 925 87

The highly metastatic amelanotic C8161 human melanoma line was found to exhibit complete dominance of its undifferentiated and metastatic phenotype in multiple somatic cell hybridization studies designed to bypass the presence of potential tumor suppressor genes. In a three armed approach involving somatic cell fusions of C8161 with recipient lines of greater differentiation, different lineage, and different tumorigenicity status, the metastatic and undifferentiated phenotype of C8161 was promiscuously dominant. In somatic cell hybrids produced between the C8161 and a group of non-metastatic human melanoma lines which exhibited melanocyte differentiation markers including S100, HMB-45, NKI/C3, and melanin, the fusions were uniformly metastatic and undifferentiated. In somatic cell hybrids of C8161 and MCF-7 the fusions exhibited an estrogen independent and unresponsive, estrogen receptor (ER) negative, and highly metastatic phenotype. In fusions between C8161 and HMS-1, an immortalized 'benign' human myoepithelial line which produced an abundant extracellular matrix (ECM) and high levels of protease and angiogenic inhibitors including maspin, tissue inhibitor of metalloproteinase-1 (TIMP-1), alpha1-antitrypsin (alpha1-AT), protease nexin II (PN-II), thrombospondin-1 and soluble basic fibroblast growth factor (bFGF) receptors, the hybrids showed complete absence of matrix, absent maspin expression, markedly decreased protease inhibitor and angiogenic inhibitor production, high levels of proteases and angiogenic factors, and a highly metastatic phenotype. In our somatic cell fusions, the human-human hybrids represented true and complete fusions and not hybrid clones selected for by loss of dominant-acting growth suppressor genes. This finding was supported by detailed comparative genomic hybridization (CGH) studies, Q-banding karyotype analysis, and autofusions of representative clones. The purposeful creation of inherently unstable human-murine fusions between C8161 and B16-F1 where loss of putative suppressor loci would be expected, resulted in fusions exhibiting decreased growth and non-metastatic behavior with progressive chromosomal loss. Neither p53, nm23, DNA methyltransferase, activated ras, fibroblast growth factor-4 (FGF-4), or epidermal growth factor receptor (EGFR) mediated the acquisition of the metastatic or undifferentiated phenotype within the C8161-human fusions. These studies are the first studies ever to successfully transfer the complete metastatic phenotype by somatic cell fusion and support the presence of a new high level regulatory pathway(s) involving dominant trans-acting factors which act pleiotropically to regulate an undifferentiated and highly metastatic phenotype.
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PMID:Evidence of a dominant transcriptional pathway which regulates an undifferentiated and complete metastatic phenotype. 936 25

To elucidate potential mechanisms involved in the increased incidence of endometrial carcinomas in tamoxifen-treated patients, we examined the in-vitro effects of tamoxifen on endometrial cancer cells. The effects of tamoxifen, alone and in combination with oestradiol, on cell proliferation, plasminogen activator (PA) activity, glycogen synthase and phosphorylase activities, p53 protein concentration, and collagenase expression were assessed in two human adenocarcinoma cell lines. These lines were the oestrogen receptor-positive (Ishikawa) cells, representing a well-differentiated endometrial adenocarcinoma, and oestrogen receptor-negative (HEC-1A) cells, derived from a poorly differentiated endometrial adenocarcinoma. Tamoxifen or oestradiol alone and their combination significantly enhanced cellular proliferation of Ishikawa but not of HEC-1A cells. Both lines produced appreciable PA activity, most of which was of the urokinase type. Tamoxifen and oestradiol stimulated this activity in Ishikawa cells but not in HEC-1A cells. The effect of oestradiol was dose-dependent in a linear fashion, while tamoxifen produced a stimulation peaking at 10(-8) M and declining at higher concentrations. Tamoxifen in combination with oestradiol exhibited a synergistic effect on proliferation and on PA activity. The response of PA extended beyond the increase in proliferation, leading to higher specific activity of PA in the tamoxifen-treated cultures. In Ishikawa cells, oestradiol also increased glycogen synthase and glycogen phosphorylase activities, while tamoxifen markedly suppressed these enzymes. Oestradiol, tamoxifen, and their combination had no apparent effect on the expression of protein p53 in Ishikawa cells, or on gelatinase activity in either Ishikawa or HEC-1A cells. The present findings imply that tamoxifen produces oestrogen-agonistic effects on cell proliferation and PA activity, and oestrogen antagonistic effects on glycogen synthase and glycogen phosphorylase activities, but fails to regulate p53 and gelatinase expression. The tamoxifen-responsive systems were only observed in oestrogen-responsive adenocarcinoma cells. Thus, only certain potential oncogenic effects of tamoxifen can be simulated in vitro, and when present, these effects are enhanced in the presence of oestradiol.
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PMID:Tamoxifen exerts oestrogen-agonistic effects on proliferation and plasminogen activation, but not on gelatinase activity, glycogen metabolism and p53 protein expression, in cultures of oestrogen-responsive human endometrial adenocarcinoma cells. 946 46

Mammalian cells in culture react to ultraviolet irradiation with the massive transcriptional activation of several genes and with the stabilization of the p53 protein. While U.V.-induced transcription of several immediate-response genes depends on U.V.-induced activation of signal transduction generated by non-nuclear mechanisms, stabilization of p53 and the transcription of several delayed-response genes are triggered by U.V.-induced DNA damage. By comparing dose responses for the activation by U.V. of delayed-responsive genes (collagenase 1, metallothionein IIA) in cells from patients with different DNA repair deficiencies (complementation groups of Xeroderma pigmentosum, Cockayne's syndrome and Trichothiodystrophy), we show here that U.V.-induced transcription of these genes does depend on pyrimidine dimers in transcribed regions of the genome (but not on damage in its silent part). Since all cells with defects in DNA repair that had been tested and which lack different enzymes, respond to U.V. with expression of these same genes, functional repair does not appear to be required for the induction of expression, and repair intermediates (which would not be identical in cells of different repair deficiency) cannot be responsible for signal generation.
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PMID:Photoproducts in transcriptionally active DNA induce signal transduction to the delayed U.V.-responsive genes for collagenase and metallothionein. 967 3

Recent studies show that the p53 tumor suppressor protein is overexpressed in rheumatoid arthritis (RA) synovium and that somatic mutations previously identified in human tumors are present in RA synovium (Firestein, G. S., Echeverri, F., Yeo, M., Zvaifler, N. J., and Green, D. R. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 10895-10900; Firestein, G. S., Nguyen, K., Aupperle, K. R., Yeo, M., Boyle, D. L., and Zvaifler, N. J. (1996) Am. J. Pathol. 149, 2143-2151; Reme, T., Travaglio, A., Gueydon, E., Adla, L., Jorgensen, C., and Sany, J. (1998) Clin. Exp. Immunol. 111, 353-3581). We hypothesize that the abnormality of p53 seen in RA synovium may contribute to joint degeneration through the regulation of human matrix metalloproteinase-1 (hMMP-1, collagenase-1) gene expression. Transcription assays were performed with luciferase reporters driven by the promoter of the hMMP-1 gene or by a minimal promoter containing tandem repeats of the consensus binding sequence for activator protein-1, cotransfected with p53-expressing plasmids. The results revealed that (i) wild-type (wt) p53 down-regulated the promoter activity of hMMP-1 in a dose-dependent fashion; (ii) four of six p53 mutants (commonly found in human cancers) lost this repression activity; and (iii) this p53 repression activity was mediated at least in part by the activator protein-1 sites found in the hMMP-1 promoter. These findings were further confirmed by Northern analysis. The down-regulation of hMMP-1 gene expression by endogenous wt-p53 was shown by treatment of U2-OS cells, a wt-p53-containing osteogenic sarcoma line, and Saos-2 cells, a p53-negative osteogenic sarcoma line, with etoposide, a potent inducer of p53 expression. p53, activated by etoposide, appears to block hMMP-1 promoter activity induced by etoposide in U2-OS cells. In summary, we have shown for the first time that the hMMP-1 gene is a p53 target gene, subject to p53 repression. Because MMP-1 is principally responsible for the irreversible destruction of collagen in articular tissue in RA, abnormality of p53 may contribute to joint degeneration through the regulation of MMP-1 expression.
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PMID:p53 down-regulates human matrix metalloproteinase-1 (Collagenase-1) gene expression. 1020 59


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