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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

UV radiation has been shown to play a role in the initiation of human cutaneous melanoma, but its role in the development of malignant melanoma to the metastatic state is not very well defined. Although previous studies have concentrated on the effect of UV-B on the host immune response, the effect of UV-B on the tumor cells was not elucidated. Here we show that UV-B can induce interleukin 8 (IL-8) mRNA and protein secretion in human cutaneous melanoma with negligible expression of IL-8. UV-B-induced IL-8 was constitutively expressed 60 days after irradiation in tumors implanted in mice. Induction of IL-8 was UV-B dose dependent and blocked by cyclohexamide, indicating that de novo protein synthesis is required for its expression. The UV-irradiated cells demonstrated enhanced tumorigenicity and metastatic potential in nude mice. The increase in tumorigenicity and metastatic ability could be explained by the increase in Mr 72,000 type IV collagenase activity and angiogenesis attributed to the induction of IL-8 after irradiation. The acquisition of the metastatic phenotype induced by UV-B could not be attributed to abnormalities in the p53 or MTS-1 (p16INK4) genes. To the best of our knowledge, this is the first report to show that UV-B can increase the aggressiveness of human cutaneous melanoma for growth and metastasis.
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PMID:Ultraviolet B irradiation promotes tumorigenic and metastatic properties in primary cutaneous melanoma via induction of interleukin 8. 754 20

Carcinogenesis requires a complex series of genetic changes often involving multiple oncogenes and the inactivation of multiple tumor-suppressor genes. We presently examined the effect of the Krev-1 tumor-suppressor gene on the tumorigenic and metastatic potential of Ha-ras-transformed cloned rat embryo fibroblast (CREF) cells. Ha-ras-transformed CREF cells are morphologically transformed and anchorage independent; produce reduced levels of nm23-H1 (a putative metastasis-suppressor gene product) and TIMP-1 (tissue inhibitor of metalloproteinase 1) transcripts and mRNA compared with CREF cells; produce increased levels of cripto, 94-kDa gelatinase/type IV collagenase (94-kDa GEL), osteopontin (OPN) and transin/stromelysin transcripts and mRNA compared with CREF cells; and are tumorigenic and metastatic in both nude mice and syngeneic rats. Ha-ras-transformed CREF cells coexpressing the Krev-1 gene display a reversion in cellular phenotype and gene expression to that of untransformed CREF cells. However, Ha-ras/Krev-1-coexpressing CREF cells retain, albeit with extended latency periods, both tumorigenic and metastatic potential that is not related directly to the final level of Ha-ras or Krev-1 mRNA or the Ha-ras p21 transforming protein. Development of metastatic potential is, however, directly correlated with a reduction in nm23-H1 and TIMP-1 transcription and mRNA levels and an enhanced expression of cripto, 94-kDa GEL, osteopontin and transin. In contrast, expression of additional tumor-suppressor genes, such as the RB gene and p53, or genes associated with tumorigenesis in other model systems, such as major excreted glycoprotein (MEP), 72-kDa gelatinase/type IV collagenase (72-kDa GEL), fibronectin (FIB), tenascin and intracellular adhesion molecule 1 (ICAM-1) is not altered in a consistent manner during in vitro transformation suppression or escape from tumorigenic and metastatic suppression. These results indicate that Krev-1 suppression of the Ha-ras-transformed/oncogenic phenotype is associated with a distinct program of gene expression changes manifested by altered rates of transcription and steady-state mRNA levels of specific oncogenic-suppressing and oncogenic-inducing genes. These data support a model of Ha-ras-induced metastasis in CREF cells that involves a direct modulation in the expression/suppression of specific combinations of oncogenic-suppressor genes and metastasis-promoting genes that are regulated coordinately in the process of tumor progression.
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PMID:Defining the critical gene expression changes associated with expression and suppression of the tumorigenic and metastatic phenotype in Ha-ras-transformed cloned rat embryo fibroblast cells. 847 44

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

p53, a tumor suppressor and a transcription factor, has been shown to transcriptionally activate the expression of a number of important genes involved in the regulation of cell growth, DNA damage, angiogenesis, and apoptosis. In a computer search for other potential p53 target genes, we identified a perfect p53 binding site in the promoter of the human type IV collagenase (also called 72-kDa gelatinase or matrix metalloproteinase 2 [MMP-2]) gene. This p53 binding site was found to specifically bind to p53 protein in a gel shift assay. Transcription assays with luciferase reporters driven by the promoter or enhancer of the type IV collagenase gene revealed that (i) activation of the promoter activity is p53 binding site dependent in p53-positive cells but not in p53-negative cells and (ii) wild-type p53, but not p53 mutants commonly found in human cancers, transactivates luciferase expression driven by the type IV collagenase promoter as well as by a p53 site-containing enhancer element in the promoter. Significantly, expression of the endogenous type IV collagenase is also under the control of p53. Treatment of U2-OS cells, a wild-type p53-containing osteogenic sarcoma line, with a common p53 inducer, etoposide, induced p53 DNA binding and transactivation activities in a time-dependent manner. Induction of type IV collagenase expression followed the p53 activation pattern. No induction of type IV collagenase expression can be detected under the same experimental conditions in p53-negative Saos-2 cells. All these in vitro and in vivo assays strongly suggest that the type IV collagenase gene is a p53 target gene and that its expression is subject to p53 regulation. Our finding links p53 to a member of the MMP genes, a family of genes implicated in trophoblast implantation, wound healing, angiogenesis, arthritis, and tumor cell invasion. p53 may regulate these processes by upregulating expression of type IV collagenase.
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PMID:Transcriptional activation by p53 of the human type IV collagenase (gelatinase A or matrix metalloproteinase 2) promoter. 934 94

This study was aimed at testing the hypothesis that the expression of proteases essentially produced by reactive stromal cells (stromelysin-3 [ST3], gelatinase A [GELA], and urokinase [uPA]) is predictive of prognosis in patients with breast cancer. This was a study of patients with node-positive and node-negative breast cancer diagnosed from 1980 to 1986 and with an average of 10 years follow-up. ST3 (665 cases), GELA, and uPA (575 cases each) expression was obtained by in situ hybridization on formalin-fixed, paraffin-embedded material using mRNA antisense probes. ST3 was expressed by 86.6% of the cases; GELA, 77.7%; and uPA, 64.7%. A significant correlation (P < .05) was found between high (more than 10%) ST3 expression and a younger age, lymph node involvement, poor nuclear grade, ductal histology, aneuploidy, and HSP-27 expression. High GELA expression was significantly associated with c-erbB2, ductal histology, and HSP-27 expression. High uPA expression correlated with poor nuclear grade, ductal histology, lack of estrogen and progesterone receptors, and p53 protein accumulation. High level of expression of all three proteases correlated significantly with each other and with cathepsin D expression by reactive stromal cells. By univariate analysis, both ST3 and uPA expression significantly predicted a shorter recurrence-free survival (ST3, P = .0199; uPA, P = .0269). By multivariate analyses, the prognostic significance was lost, most particularly at longer term. This study adds support to the concept that protease expression by reactive stromal cells is related to cancer cell characteristics but that their contribution to cancer progression is marginal.
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PMID:Prognostic significance of stromelysin 3, gelatinase A, and urokinase expression in breast cancer. 974 15

The protein MMP-2 (type IV collagenase) belongs to the family of metalloproteinases. Its function is related to cellular matrix degradation including basement membrane type IV collagen. Its presence in the neoplastic cells might enhance its capacity for dissemination. To find out some of its clinico-pathological and immunohistochemical behavior, 98 adenocarcinomas of the stomach were immunohistochemically studied, in search for MMP-2 in neoplastic cells. The results showed a correlation between MMP-2 with parietal depth of infiltration (p = 0.03) and with metastases in regional lymph nodes (p = 0.05). On the other hand, no correlation was found with sex, gastric localization, size of the tumor, histological type or grade neither with expression of MIB-1, c-erbB-2 nor p53 proteins, recurrence nor 5 year survival or no recurrency.
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PMID:[MMP-2 expression (type IV collagenase) in gastric cancer]. 1034 87

Gelatinase A, also denoted matrix metalloproteinase 2, plays multiple critical roles in the neoplastic process, including facilitation of neoangiogenesis and formation of distal metastases. The transcriptional regulation of the gelatinase A gene is under the control of strong, evolutionarily conserved cis-acting enhancer elements, designated the r2 (human) or RE-1 (rat), that harbor contiguous binding motifs for the transcription factors activating protein-2 (AP2), p53, and YB-1. Using recombinant transcription factors, complex patterns of RE-1 binding were observed by electrophoretic mobility shift assay. Increased complex formation was detected with the AP2/YB-1 and AP2/p53 combinations, while YB-1 competed with p53 for binding. The combination of AP2, p53, and YB-1 yielded novel ternary complexes, particularly when binding to single-stranded RE-1 probes. Transient transfection of hepatocellular carcinoma cell lines with a series of gelatinase A luciferase reporter constructs were in accordance with the binding patterns determined by electrophoretic mobility shift assay. Combined AP2 and p53 increased gelatinase A luciferase reporter activity significantly, and the inclusion of YB-1 yielded further increase in both reporter activity and secreted levels of gelatinase A protein. YB-1 and p53 expression are increased following multiple genotoxic stresses, including irradiation, and the synergistic interactions of these induced transcription factors with the widely expressed AP2 protein provide a probable pathophysiologic mechanism for the enhanced tumor cell synthesis of gelatinase A induced by radiation.
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PMID:Combinatorial interactions of p53, activating protein-2, and YB-1 with a single enhancer element regulate gelatinase A expression in neoplastic cells. 1197 33

Gelatinase A transcriptional regulation is the consequence of combinatorial interactions with key promoter and enhancer elements identified within this gene. A potent 40 bp enhancer response element, RE-1, located in the near 5' flanking regions of the rat and human gelatinase A genes drives high-level expression in glomerular mesangial cells (MCs). Southwestern-blot analysis of MC nuclear extracts revealed specific interactions of RE-1 with at least four proteins, of which three have been identified as p53, activator protein 2 and the single-stranded DNA-binding factor Y-box protein-1 (YB-1). In the present study, we report the identification of a fourth 17 kDa RE-1-binding protein as the rat homologue (nm23-beta) of the human nm23-H1 metastasis suppressor gene. Recombinant nm23-beta protein bound only the single-stranded forms of the RE-1 sequence. Mutagenesis revealed direct interaction of nm23-beta with a repeat sequence, 5'-GGGTTT-3', shown previously to specifically interact with YB-1 [Mertens, Harendza, Pollock and Lovett (1997) J. Biol. Chem. 272, 22905-22912], and recombinant nm23-beta protein competed for single-stranded YB-1 binding. Transient transfection of MC with an nm23-beta expression plasmid within the context of a RE-1/simian virus 40 promoter/luciferase reporter yielded a concentration-dependent repression (80-90%) of luciferase activity in MC and Rat1 fibroblasts. A similar pattern of nm23-beta repression was demonstrated within the context of the RE-1/homologous gelatinase A promoter. Co-transfection of nm23-beta blocked YB-1-mediated activation of transcription and expression of gelatinase A. Nm23-beta may be an important physiological regulator of gelatinase A transcription that acts by competitive interference with the single-stranded transactivator YB-1. Gelatinase A is a key mediator of tumour metastasis, suggesting that competitive suppression of transcription by nm23-beta (or the human nm23-H1) may be a component of the reduced metastatic capabilities of cells expressing high levels of this protein.
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PMID:Tumour metastasis suppressor, nm23-beta, inhibits gelatinase A transcription by interference with transactivator Y-box protein-1 (YB-1). 1201 Jan 25

Wilms' tumour is a pediatric neoplasm exhibiting histologic features of developing kidney. Although the majority of Wilms' tumour patients are treated effectively, approximately 15% develop metastases and of these, 30% succumb to their disease. The biologic factors governing Wilms' tumour metastasis are largely unknown. Attempts at deriving representative Wilms' tumour cell lines, which could facilitate functional studies, have only been partially successful thus far. We now report on derivation and characterization of a Wilms' tumour cell line, WiT 49, from a first-generation xenograft of a human Wilms' tumour lung metastasis. WiT 49 recapitulates the phenotype of the parent tumours (primary and lung metastasis) and expresses normal WT1, overexpresses IGFII and carries a frequently identified p53 mutation. We recently reported overexpression of hepatocyte growth factor(HGF) and its receptor met in a series of Wilms' tumours with higher levels in homotypic metastatic cases. We therefore examined WiT 49 for expression of HGF/met and for met signaling targets associated with cell adhesion and cytoplasmic mediators of transcription using Western blot, co-immunoprecipitation, immunofluorescence labeling and zymography. Our results show co-expression of HGF and met protein, absence of E-cadherin, high levels of beta-catenin co-immunolocalized to met at the cell membrane and moderate levels of gamma-catenin and ezrin protein expression. After cell fractionation, beta-catenin was detected in the cytoplasm and nuclei of WiT 49 with relatively higher levels in the cytoplasm as compared to nuclei. Examination of MMP expression in WiT 49 showed constitutive activation of MMP 9 and latent MMP 2 supporting possible beta-catenin-mediated transcriptional activation. The WiT 49 cell line responded to recombinant human HGF by an increase in the expression of the met receptor, recruitment of the Gab-1 adapter protein to met and release of bound beta-catenin from met. Our studies therefore establish WiT 49 as a representative Wilms' tumour cell line derived from a lung metastasis that co-expresses HGF/met and shows absence of the cadherin-catenin complex supporting a role for these factors in regulation of the invasive and metastatic phenotype in Wilms' tumour.
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PMID:Derivation and characterization of a Wilms' tumour cell line, WiT 49. 1450 35

The objective of this immunohistochemical study was to explore the roles of Ki67 and p53 in conjunction with matrix metalloproteinase-2 and matrix metalloproteinase-9, tissue inhibitors of metalloproteinase-1 and tissue inhibitors of metalloproteinase-2 in a series of 157 cases of skin melanomas. Elevated Ki67 expression and positive staining for p53 correlated to the propensity to metastasize (P = .016) and to declined disease-specific survival, as well as to shortened recurrence-free survival. In patients with a high immunoreaction for Ki67, the 10-year disease-specific survival was 39% compared with 73% in patients with a low Ki67 expression (P = .03). In cases with a positive p53 expression in melanoma cells, the 10-year disease-specific survival was 59% compared with 76% in patients with a negative immunoreaction for p53 (P = .005). Overexpression of the matrix metalloproteinase 2 protein in conjunction with overexpression of Ki67 characterized melanomas with high metastatic potential and was associated with declined survival with a 10-year disease-specific survival of 33% compared with 85% in the cases with low matrix metalloproteinase-2 and low Ki-67 levels (P = .002). Similarly, in cases with overexpression of matrix metalloproteinase-2 and a positive immunoreaction for p53, the 10-year disease-specific survival was only 42% compared with 80% in patients with matrix metalloproteinase-2 less than 20% and a negative immunostaining for p53 (P < .001). The presence of all 3 adverse prognostic factors was prognostically more significant than any marker alone with a 10-year survival of only 28%. This combination of determining matrix metalloproteinase 2, Ki67, and p53 immunoreactive proteins could be beneficial in the selection of high-risk melanoma patients for future adjuvant trials.
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PMID:A prognostic index in skin melanoma through the combination of matrix metalloproteinase-2, Ki67, and p53. 2133 17


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