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)

Two hundred and eleven surgically resected primary lung tumors were studied immunohistochemically. According to histologic type, they were 129 adenocarcinomas, 56 squamous cell carcinomas, 4 small cell carcinomas, 8 large cell carcinomas, 8 adenosquamous cell carcinomas, 5 so-called carcinosarcomas and 2 other tumors. Immunohistochemical expression of p53 and bcl-2 was studied in relation to the disease-free survival. Among the 211 patients with lung cancer, 109 were positive for p53 expression, and there was no significant relationship between p53 expression and sex, or clinicopathological stage and size of the tumor, although the patients with squamous cell carcinoma had a significantly higher frequency of p53 expression than those with adenocarcinomas. The frequency of p53 expression was significantly higher in the patients with poorly differentiated adenocarcinomas than in those with other histologic types. Seventy four of the 211 patients were positive for bcl-2 expression and bcl-2 expression was higher in the stage I patients and patients with small lung tumors 2cm or less in diameter than in the other patients. The patients with adenocarcinoma had a higher frequency of expression than those with squamous cell carcinoma but no difference was found in the histological differentiation of the tumor. The 5-year survival of patients positive for p53 expression was poorer than that of those with negative expression and the survival rate was higher in the patients positive for bcl-2 expression than in those with negative expression. These findings suggested that the expression of p53 and bcl-2 is a useful marker of follow-up and prognosis, but will require more data concerning the mechanism of carcinogenesis. Seven cases of primary lung cancer were examined for genetic abnormality of the p53 gene. cDNA was synthesized from total RNA of primary tissues of lung cancer using oligo (dT) primer and reverse transcriptase and polymerase chain reaction (RT-PCR), and PCR-single strand conformation polymorphism (SSCP) analysis were performed. Five patients gave a positive result upon PCR-SSCP analysis of the p53 gene. To confirm the results of PCR-SSCP analysis, their nucleotide sequences were further analyzed and four of them had point mutations at different codons (154, 176, 207, 236) and one had deletion of one nucleotide (245) in exon 5 and 8. Fifteen percent of 26 patients with small peripheral lung adenocarcinomas less than 2cm in diameter were already advanced in stage and various factors such as vascular invasion, pleural involvement and degree of scar grade were higher than in patients with clinicopathological stage I. In advanced cases, the frequencies of p53 expression was higher than in stage I cases. Concerning the relationship of the degree of scar grade to PDGF-B expression, we demonstrated the production of PDGF-B protein immunohistochemically and the expression of PDGF-B-mRNA by In situ hybridization in the adenocarcinoma cells and macrophages of the lung tumors. However, no significant correlation was observed between the degree of PDGF-B expression and collagen production in the fibrotic focus.
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PMID:[Clinicopathological study on primary lung cancer--immunohistochemical expression of p53 suppressor gene and bcl-2 oncogene in relation to prognosis]. 869 38

Chronic myeloid leukemia is characterized by the Philadelphia (Ph1) translocation t(9;22) that generates a hybrid gene, bcr/abl, translated to a Mr210,000 tyrosine kinase (p210bcr/abl) with transforming activity for hematopoietic cells. Hematopoietic cell transformation by p2l0bcr/abl seems to involve activation of the Ras signaling pathway by at least two different signaling intermediates, growth factor receptor-bound protein 2 and Src homology and collagen protein, but additional signaling proteins are likely to be required as well. In an effort to identify additional phosphoproteins activated by p210bcr/abl, we studied the murine, interleukin 3-dependent, myeloid cell line, 32D, and a bcr/abl-transfected, factor-independent subline, 32Dp210. The analysis of whole-cell lysates of 32D and 32Dp210 cells showed that several proteins with a molecular weight of Mr50,000-60,000 were phosphorylated on tyrosine residues in 32Dp210 cells. Because Src family kinases have an apparent molecular weight of Mr50,000-60,000, we asked whether they could become activated by p2l0bcr/abl. Two Src family kinases, p53/56lyn and p59hck, showed a severalfold higher phosphokinase activity in 32Dp210 cells than in 32D cells. Coimmunoprecipitation experiments with anti-Lyn, anti-Hck, and anti-Abl antibodies demonstrated an intracellular association of p210bcr/abl with p53/56lyn and p59hck. Moreover, the phosphokinase activity of p53/56lyn was higher in bcr/abl-positive myeloid cell lines (K562, BV173, and LAMA84) than in the bcr/abl-negative myeloid cell line JOSK-M. In conclusion, the results show that p210bcr/abl induces the activation of at least two Src family kinases, P53/56lyn and p59hck, in myeloid cells. These findings extend the range of potential targets of p210bcr/abl that might mediate its transforming effects.
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PMID:Activation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells. 875 31

To understand the specific cell type responsible for the synthesis of basement membrane components of the salivary gland, the effects of transforming growth factor (TGF)-beta 1 on morphological change, cellular proliferation and collagen synthesis were examined in these immortalized duct and myoepithelial cell clones, and the expression forms of their TGF-beta receptors analysed. When TGF-beta 1 was added to the cell clones in vitro, it induced a morphological alteration, with flattening in myoepithelial but not in duct cells. Although the growth of Mv1Lu mink lung epithelial cells was almost completely inhibited by TGF-beta 1, the duct and myoepithelial cells were partially resistant to such inhibition. By immunoblot analysis of immunoprecipitates, p53 was found bound to the simian virus-40 large T antigen, suggesting a functional loss of p53 in regulation of cell-cycle arrest. In the cloned myoepithelial cells but not the duct cells, TGF-beta 1 stimulated the production of type IV collagen. To attempt to understand the distinct responsiveness of cell clones to TGF-beta 1, the expression forms of TGF-beta receptors were examined by affinity cross-linking. Although the intensities of the cross-linked bands of the TGF-beta type II and type III receptors, particularly the type II, were weaker in the duct than the myoepithelial cell clones, the expression of the type II receptor mRNA was consistently detected in both clones. Accordingly, the reduction of TGF-beta 1 binding may have occurred at the post-transcriptional level. These findings imply that the cloned myoepithelial cells but not the cloned duct cells produce type IV collagen in response to TGF-beta 1 through the receptor-mediated signal transduction pathway, which is presumably disrupted in the cloned duct cells.
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PMID:Different signalling pathways involved in transforming growth factor-beta 1-induced morphological change and type IV collagen synthesis in simian virus-40-immortalized normal human salivary gland duct and myoepithelial cell clones. 880 3

In a previous report, we observed by light microscopy the extracellular matrix in 51 vulvar squamous carcinomas and found that some tumors has a prominent stromal response in the form of a regional or diffuse zone of extracellular myxoid matrix containing immature collagen and fibroblasts at the tumor-stromal junction. These tumors were associated with clitoral involvement, ulcerative nonexophytic growth pattern, older age groups, poorer survival rate, and more extensive lymph node metastases than when prominent fibromyxoid stromal response (PFSR) was absent. This behavior was demonstrated despite the fact that these tumors were not larger, more deeply invasive, or of higher grade than when PFSR was absent. In the current immunohistochemical study, we examined cytokine, cell adhesion receptor, and tumor suppressor gene expression in 50 vulvar squamous carcinomas using a panel of antibodies to identify any potential role of these proteins in the development of a PFSR. Semiquantification of expression into none, focal (< 25% of cells showing expression), regional (25-50%), and diffuse (> 50%) patterns revealed PFSR to be statistically associated with high CD44, transforming growth factor (TGF) beta 3, and p53 protein expression, but not with fibroblast growth factor, epidermal growth factor, epidermal growth factor receptor, or E-cadherin expression. When expression of CD44 and either stromal or tumor TGF-beta 3 expression was high, i.e., regional or diffuse in distribution, 15 (50%) of 30 cases were associated with PFSR. In contrast, only 1 (7%) of 14 cases was associated with PFSR when expression was high for only one of these two proteins and none of 3 cases was associated with response when expression was low for both proteins (p = 0.005). Furthermore, in cases showing high expression for both TGF-beta 3 and CD44, PFSR was found in 13 (72%) of 18 cases when p53 expression was diffuse compared with 2 (17%) of 12 cases when expression was less (p = 0.01). Since TGF-beta acts mitogenically for fibroblasts and has been shown to be an inhibitor of epithelial cell growth, its high expression in a carcinoma with PFSR would suggest loss of effect on the epithelial component but an intact effect on the stroma. Since CD44 is known to act as a receptor for hyaluronic acid, which is a prominent stromal component and known to play an important role in cell mobility and tumor aggressiveness, its high expression in association with PFSR would suggest a role of CD44 overexpression in altered hyaluronate metabolism with accelerated tumor cell migration and subsequent distal spread. The current study demonstrates that alterations in cytokine and cell adhesion receptor status variably occur in vulvar squamous carcinoma and that such alterations may affect tumor morphology and behavior.
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PMID:Cytokine, cell adhesion receptor, and tumor suppressor gene expression in vulvar squamous carcinoma: correlation with prominent fibromyxoid stromal response. 888 79

SV40 T antigen (LT) is an oncoprotein that inactivates nuclear regulators such as retinoblastoma (RB) family proteins and p53. We recently reported that in Madin-Darby canine kidney (MDCK) epithelial cells the binding of LT to RB family proteins results in a massive apoptosis and a concomitant down-regulation of c-myc. Here, we show that LT causes loss of epithelial differentiation and induces invasiveness. MDCK cells expressing wild-type LT, but not mutants unable to bind RB, exhibit a fibroblast-like morphology, show a strong down-regulation of the vHNF1 transcription factor and acquire invasive properties. The stable retransformation of MDCK(LT) with a RB and/or c-myc-expressing vector restores the expression of epithelial characteristics. Our data therefore suggest an important role for RB and c-myc in modulating the epithelial phenotype both during normal tissue development and in invasive processes. In addition, when grown in collagen gels, the MDCK(LT) cells form branching tubules, and their conditioned media produce the scattering of monolayer cultured MDCK cells. These last properties are reminiscent of those induced by hepatocyte growth factor/scatter factor (HGF/SF). Moreover, the HGF/SF protein was detected by Western blotting in the MDCK(LT)-conditioned medium. The production of HGF/SF is specifically induced by LT-RB inactivation, because Ras transformation of MDCK cells fails to induce the production of this factor. These results demonstrate that inactivation of RB family proteins in these cells is at the origin of a HGF/SF autocrine loop.
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PMID:Inactivation of retinoblastoma family proteins by SV40 T antigen results in creation of a hepatocyte growth factor/scatter factor autocrine loop associated with an epithelial-fibroblastoid conversion and invasiveness. 904 Sep 38

Animal models have an important role in cutaneous research. The guinea pig has proven to be a useful model in a wide spectrum of these cutaneous studies; however, its usefulness is often compromised by the need for depilation. A euthymic hairless guinea pig (HGP) model avoids the problems associated with depilation. Morphologically, as in human skin, these animals have a multi-cell-layer epidermis. Proliferation kinetic studies, as well as documentation of the degree of immunologic cross-reactivity between available antibodies to human cutaneous antigens, could extend the usefulness of this animal model. We performed a battery of anti-human antibodies on formalin fixed tissue, to a variety of antigens present within the skin and on inflammatory cells. These included CD3, UCHL-1, OPD4, L-26, KP-1, Factor XIIIa, S-100 protein, cytokeratin (AE1, AE3 and CK1), CAM 5.2, vimentin, CD 34, Factor VIII, fibronectin, SM actin, collagen IV, laminin, Bcl-2, p53, Ki-67, and PCNA. Cross-reacting antibodies included: CD3, S-100 protein, cytokeratin (AE1, AE3 and CK1), vimentin, Factor VIII, SM actin, collagen IV, p53, Ki-67, and PCNA. Although this battery of antibodies is limited, the markedly increased staining of Ki-67 and PCNA within keratinocytes in the epidermis as compared to normal human skin reflects a high proliferative rate. In addition, positive staining for p53, Ki-67, and PCNA may be useful in studying effects on cell cycle kinetics and apoptosis.
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PMID:Evaluation of cross-reacting anti-human antibodies in the euthymic hairless guinea pig model (HGP) suggests that the HGP may be a model for the study of proliferative skin disease. 913 82

Loss of attachment may induce apoptosis in epithelial cells, but it is unclear whether substrate adhesion modulates apoptosis triggered by genotoxic agents such as ultraviolet radiation (UV). To investigate this issue, we plated neonatal human keratinocytes on different substrates and irradiated them with UVB. DNA strand breaks were nick-labeled to identify apoptotic nuclei. Keratinocytes grown in monolayers were less susceptible to UV-induced apoptosis than were cells freshly seeded on glass (ED50 2130 +/- 96 J per m2, mean +/- SD, versus 131 +/- 96 J per m2, mean +/- SD, respectively). This phenomenon depended on differences in integrin-mediated adhesion, because blocking of integrin beta1 with a monoclonal antibody increased sensitivity of keratinocyte monolayers to UV and an increase in beta1 integrin receptor occupancy by plating on fibronectin, type IV collagen, or keratinocyte-derived extracellular matrix diminished the UV-dependent apoptosis. Down-regulation of p53 with an anti-sense oligonucleotide did not affect apoptosis in glass-plated keratinocytes but effectively suppressed apoptosis in keratinocytes adhering via beta1 integrin. Thus, in addition to the known p53-dependent pathway, UV was able to induce a p53-independent apoptosis that could be blocked by integrin-mediated cell attachment (the integrin-sensitive pathway). The susceptibility to the p53-dependent apoptosis, but not to the integrin-sensitive process, varied among keratinocytes of different clonogenic potential: transit amplifying cells > stem cells > terminally differentiated cells. The p53-independent integrin-sensitive apoptotic pathway may provide an additional mechanism counteracting UV carcinogenesis in the skin.
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PMID:Two pathways for induction of apoptosis by ultraviolet radiation in cultured human keratinocytes. 924 2

An organotypic, tridimensional cell culture, also called a raft system, was used to study the influence of fibroblasts on epithelial carcinogenesis in a cell line derived from laryngeal squamous cell carcinoma and harboring a mutated p53. Differences between the effects of normal fibroblasts and those of tumor-derived fibroblasts were compared by means of fibroblasts taken from the normal skin and from the tumor of a cancer patient and cultivated with epithelial carcinoma cells in an organotypic culture. To study cell contact-mediated changes, the fibroblasts were either simply embedded in collagen matrix or additionally brought into direct contact with epithelial cells. Control epithelial cells were cultivated without any fibroblasts in an organotypic model. A protein panel [p53, p21, PCNA, bcl-2, Ki67, total cytokeratin (CK), CK 8, CK 10, CK 17, CK 18, CK 19, vimentin] involved in cell cycling and epithelial differentiation was assessed immunocytochemically in all organotypic cultures with fibroblasts, in tumor cells cultivated as a monolayer, and in the original tumor sample. The most dysplastic phenotype was obtained when tumor-derived fibroblasts were used in direct contact with epithelial cells, whereas the most benign phenotype was seen when skin fibroblasts had no contact with them. The intensive staining seen for p53 can be explained by p53 mutations also reflecting the weak expression of p21 and abundant expression of PCNA. The intensive Ki67 staining seen in all sections paralleled that of PCNA and marked active cellular proliferation. The CK staining pattern seen in cultured epithelia toward embryonic CKs, CK 8 and CK 18, suggested a simple epithelial phenotype. CK 19 was found only in the epithelium where no direct contacts had occurred. Vimentin expression increased when the raft epithelium was shifting toward a more benign phenotype. The results stress the importance of the origin of fibroblasts as well as the role of direct cellular contacts in modifying the epithelial phenotype even when the epithelial cells are malignant.
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PMID:Fibroblasts can modulate the phenotype of malignant epithelial cells in vitro. 928 67

Sulfur mustard (2,2-dichlorodiethyl sulfide, HD) is a chemical warfare agent that is a threat to both troops and civilians. The focus of HD research has been on intracellular adduct formation leading to apoptosis and/or necrosis in cutaneous lesions. However, there is work which suggests that HD may have a more direct effect on the basement membrane zone. Immunohistochemical staining to desmosomal proteins, cellular fibronectin, laminin 1, laminin 5, collagen IV, collagen VII, p53, Bcl-2, and PCNA was performed on weanling pig skin exposed to vesicating doses of HD, GB3, an antibody to laminin 5, showed a progressive decrease with loss of expression during the time period of clinical vesiculation. The other basement membrane proteins showed no change or inconsistent changes. PCNA, and p53 staining increased in the overlying epidermis in areas of vesiculation without significant necrosis. Bcl-2 positive cells were decreased or absent after exposure. This study implicates laminin 5 as the main basement membrane protein affected acutely by HD exposure. The patterns of staining of PCNA, Bcl-2, and p53 within the epidermis suggest that apoptosis and cellular necrosis both may play a role in cell death secondary to HD.
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PMID:Immunohistochemical studies of basement membrane proteins and proliferation and apoptosis markers in sulfur mustard induced cutaneous lesions in weanling pigs. 930 45

Expression of intermediate filaments (IFs) has been suggested to be a reliable marker for differentiating epithelial and non-epithelial tumors. Moreover, the c-erbB-2 and p53 genes are considered to be involved relatively early in the process of human carcinogenesis. In order to elucidate the origin of uterine carcinosarcomas, we analyzed IF, c-erbB-2 and p53 expression in and the ultrastructural characteristics of clones derived from a human uterine-carcinosarcoma cell line, EMTOKA. The expression of IFs and other proteins in the EMTOKA clones was identical to that in the EMTOKA cell line. It and its 7 clones all expressed cytokeratins 8, 17, 18 and 19, vimentin, epithelial membrane antigen, S-100, myoglobin, type-II collagen, alpha-smooth-muscle actin, placental alkaline phosphatase and epidermal-growth-factor receptor. The c-erbB-2 and p53 expression levels of all the cell types of the EMTOKA cell line and its clones were the same. Interestingly, an ultrastructural study showed that the EMTOKA cell line and its clones at early and late passages possessed the characteristics of epithelial cell types without either transitional forms between the epithelial and stromal components or differentiation into sarcomatous components. The results of this study lend particular support to the combination tumor hypothesis that a precursor (stem) cell gives rise both to epithelial and to mesenchymal components during the histogenesis of uterine carcinosarcoma, the epithelial component of which appears to be dominant, suggesting that the established cell lines derived from a common stem cell.
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PMID:Uterine carcinosarcoma is derived from a single stem cell: an in vitro study. 931


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