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)

Basaloid-squamous carcinoma (BSC) of the esophagus is a rare but interesting neoplasm that occurs primarily in the upper aerodigestive tract. In this study, we reviewed 371 cases of esophageal malignancies and detected seven cases (1.9%) of BSC. The clinicopathologic features, light and electron microscopic findings, and immunohistochemical localization of various differentiation-related antigens, including cytokeratin (CK) subtypes, p53, and epidermal growth factor receptor (EGFR), were examined. DNA ploidy was also determined in an effort to characterize the biologic features of these tumors. The tumors were classified as stage I (n = 1), IIB (n = 3), III (n = 2) or IV (n = 1). Six patients had lymph node metastasis, in four the metastatic carcinoma exhibited basaloid components. Histologically, all the tumors displayed a biphasic pattern of basaloid and squamous components. The former predominated in three cases, the latter in four cases. All the tumors contained solid growth of basaloid cells with microcystic patterns and stromal hyalinosis as well as palisading of cells. Ultrastructurally, markedly replicated basement membrane was observed. Immunohistochemistry revealed staining with only CK 14 and CK 19 antibodies in the periphery of the basaloid tumor nests. These antibodies were also positive in the basal layer of normal esophagus. Diffuse immunoreactivity for EGFR was demonstrated in all the tumors. Five tumors displayed p53 nuclear immunoreactivity. All of the basaloid components demonstrated aneuploidy by DNA image cytometry. We conclude that BSC is a distinct type of esophageal carcinoma that should be differentiated from the usual types of esophageal carcinoma and may be associated with aggressive biologic behavior.
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PMID:Basaloid-squamous carcinoma of the esophagus. A clinicopathologic, DNA ploidy, and immunohistochemical study of seven cases. 860 12

After interferon (IFN) treatment of patients with condyloma acuminatum, groups clinically proven to be responders or nonresponders were selected, and cellular parameters that might influence the clinical response were studied in pretreatment biopsies by reverse transcription polymerase chain reaction (RT-PCR). The nonresponders were found to express higher amounts of cellular proliferative markers, such as proliferating cell nuclear antigen (PCNA), cyclin A, and cdc 2 kinase, but lower levels of growth suppressor genes (TGF-beta 1, TGF-beta 2 and p53) before IFN treatment. The responders retained the epidermal keratinization, except for some signs of hyperproliferation (K6, K16 cytokeratins). In addition, the nonresponders showed a shift in the keratinization pattern to a mucosal or fetal type, as evidenced by high expression of the K18, K6, K16 and K13 cytokeratins but decreased K5, K14 and K10 levels before treatment. The expression of the human papillomavirus (HPV) genes is consistent with these differentiation patterns. The crucial conclusion to be drawn from this study is that those condylomas whose pretreatment phenotype most closely resembles that of normal epidermis respond to IFN treatment, whereas those more akin to nonkeratinizing epithelia fail to respond, i.e. the resistance of condylomas to IFN treatment is correlated with dedifferentiation.
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PMID:Response to interferon treatment decreases with epidermal dedifferentiation in condylomas. 886 92

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

AP-1 transactivation appears to be required for mouse JB6 cell neoplastic transformation induced by the tumor promoter TPA or epidermal growth factor (EGF). Exposure to AP-1 transrepressing retinoids and glucocorticoids and expression of a dominant negative c-jun (TAM67) blocked tumor promoter-induced AP-1 transactivation and neoplastic transformation. The aim of the present study was to extend the inquiry of the role of AP-1 and other transcription factors to human neoplastic progression. Expression of human papillomavirus (HPV) 16 or 18 E6 and E7 immortalizes human keratinocytes and inhibits serum/calcium-stimulated differentiation. Further transformation by v-fos co-expression renders these keratinocytes tumorigenic in nude mice. We have analysed two series of E6/E7 immortalized human keratinocyte cell lines that show progressing phenotypes ranging from differentiation sensitive to anchorage-independent to tumorigenic in nude mice. We analysed the activities of AP-1 and NF-kappaB which may 'cross-talk'. Both DNA binding and transactivation of AP-1 and NF-kappaB transcription factors showed elevation in the anchorage-independent (16RH) and tumorigenic (18 v-fos) keratinocyte lines compared to the less progressed but immortalized cell lines. HPV E7 was expressed at a constant level shown by quantitative RT-PCR in both the more and the less progressed lines, indicating that E7 is not the factor limiting this progression. Blocked shift/supershift analysis indicates that Fos family member proteins especially Fra-1 and Fra-2 are related to progression and no changes found in the Jun family member proteins although they are present in the AP-1/DNA binding complex. When a dominant negative mutant c-jun driven by a human keratin 14 promoter was co-transfected with AP-1 or NF-kappaB reporters, both AP-1 and NF-kappaB activities were suppressed in the more progressed cell lines 16RH and 18 v-fos but not in the less progressed 16RL or 18 cell lines. Overexpression of the same dominant negative c-jun did not inhibit p53 dependent reporter transactivation, indicating the specificity of inhibition of AP-1 and NF-kappaB transactivation in the HPV-immortalized cells. Stable transfectants of this mutant c-jun in the two more progressed cell lines 16RH and 18 v-fos showed reduced AP-1 and NF-kappaB activation and reduced anchorage-independent growth. Together, these results indicate that activation of AP-1, NF-kappaB or both may contribute to neoplastic progression in HPV immortalized human keratinocytes and that specific targeting of the elevated levels seen in benign or malignant tumors might be effective for prevention or treatment of human cancer.
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PMID:Expression of dominant negative Jun inhibits elevated AP-1 and NF-kappaB transactivation and suppresses anchorage independent growth of HPV immortalized human keratinocytes. 965 37

The MDM2 proto-oncogene is overexpressed in human tumours and regulates the activities of the tumour suppressors p53 and pRB. We created mice that overexpress MDM2 under the control of the CMV promoter. These mice did not display an increased tumour incidence, but rather a specific skin phenotype, characterized by desquamation and hyperkeratosis. Transgenic MDM2 was found to be overexpressed in the epidermis, a tissue that normally expresses high levels of MDM2. The phenotype appeared during the first week after birth and then lessened with age, closely following the level of expression of the transgene. MDM2 overexpression was associated with an increase in proliferation in the basal layer, thickening of the epidermis, altered expression of the differentiation markers cytokeratin CK14, CK10 and CK1, and a decrease in the size and the number of granules that contain products of differentiation. Transgenic mice on a p53 null background displayed similar although not identical changes, showing that the effects of MDM2 are to a certain degree p53 independent. The skin is a major site of MDM2 expression in mice, raising the possibility that MDM2 overexpression perturbs the normal pattern of MDM2 expression and inhibits differentiation of the epidermis.
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PMID:MDM2 overexpression generates a skin phenotype in both wild type and p53 null mice. 1005 Aug 79

The members of the large keratin family of cytoskeletal proteins are expressed in a carefully regulated tissue- and differentiation-specific manner. Although these proteins are thought to be involved in imparting mechanical integrity to epithelial cells, the functional significance of their complex differential expression is still unclear. Here we provide new data suggesting that the expression of particular keratins may influence cell proliferation. Specifically, we demonstrate that the ectopic expression of K10 inhibits the proliferation of human keratinocytes in culture, while K16 expression appears to promote the proliferation of these cells. Other keratins, such as K13 or K14, do not significantly alter this parameter. K10-induced inhibition is reversed by the coexpression of K16 but not that of K14. These results are coherent with the observed expression pattern of these proteins in the epidermis: basal, proliferative keratinocytes express K14; when they terminally differentiate, keratinocytes switch off K14 and start K10 expression, whereas in response to hyperproliferative stimuli, K16 replaces K10. The characteristics of this process indicate that K10 and K16 act on the retinoblastoma (Rb) pathway, as (i) K10-induced inhibition is hampered by cotransfection with viral oncoproteins which interfere with pRb but not with p53; (ii) K10-mediated cell growth arrest is rescued by the coexpression of specific cyclins, cyclin-dependent kinases (CDKs), or cyclin-CDK complexes; (iii) K10-induced inhibition does not take place in Rb-deficient cells but is restored in these cells by cotransfection with pRb or p107 but not p130; (iv) K16 efficiently rescues the cell growth arrest induced by pRb in HaCaT cells but not that induced by p107 or p130; and (v) pRb phosphorylation and cyclin D1 expression are reduced in K10-transfected cells and increased in K16-transfected cells. Finally, using K10 deletion mutants, we map this inhibitory function to the nonhelical terminal domains of K10, hypervariable regions in which keratin-specific functions are thought to reside, and demonstrate that the presence of one of these domains is sufficient to promote cell growth arrest.
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PMID:Modulation of cell proliferation by cytokeratins K10 and K16. 1008 75

Balancer chromosomes are genetic reagents that are used in Drosophila melanogaster for stock maintenance and mutagenesis screens. Despite their utility, balancer chromosomes are rarely used in mice because they are difficult to generate using conventional methods. Here we describe the engineering of a mouse balancer chromosome with the Cre-loxP recombination system. The chromosome features a 24-centiMorgan (cM) inversion between Trp53 (also known as p53) and Wnt3 on mouse chromosome 11 that is recessive lethal and dominantly marked with a K14-Agouti transgene. When allelic to a wild-type chromosome, the inversion suppresses crossing over in the inversion interval, accompanied by elevated recombination in the flanking regions. The inversion functions as a balancer chromosome because it can be used to maintain a lethal mutation in the inversion interval as a self-sustaining trans-heterozygous stock. This strategy can be used to generate similar genetic reagents throughout the mouse genome. Engineering of visibly marked inversions and deficiencies is an important step toward functional analyses of the mouse genome and will facilitate large-scale mutagenesis programs.
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PMID:Engineering a mouse balancer chromosome. 1043 Dec 43

A major objective of current cancer research is to develop a detailed molecular characterization of tumor cells and tissues that is linked to clinical information. Toward this end, we have identified approximately one-quarter of all genes that were aberrantly expressed in a breast cancer cell line using differential display. The cancer cells lost the expression of many genes involved in cell adhesion, communication, and maintenance of cell shape, while they gained the expression of many synthetic and metabolic enzymes important for cell proliferation. High-density, membrane-based hybridization arrays were used to study mRNA expression patterns of these genes in cultured cells and archived tumor tissue. Cluster analysis was then used to identify groups of genes, the expression patterns of which correlated with clinical information. Two clusters of genes, represented by p53 and maspin, had expression patterns that strongly associated with estrogen receptor status. A third cluster that included HSP-90 tended to be associated with clinical tumor stage, whereas a forth cluster that included keratin 14 tended to be associated with tumor size. Expression levels of these clinically relevant gene clusters allowed breast tumors to be grouped into distinct categories. Gene expression fingerprints that include these four gene clusters have the potential to improve prognostic accuracy and therapeutic outcomes for breast cancer patients.
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PMID:Linking gene expression patterns to therapeutic groups in breast cancer. 1078 89

Non-squamous cell carcinoma is a rare but distinct neoplasm of the upper aerodigestive tract. Among these carcinomas, basaloid-squamous cell carcinoma (BSCC) has frequently been confused with adenoid cystic carcinoma (ACC) and mucoepidermoid carcinoma of the upper aerodigestive tract. In this study, we examined immunohistochemically the expression of differentiation-related substances, including cytokeratin (CK) subtypes, p53 and p27, and cell adhesion-related molecules E-cadherin and alpha-catenin to clarify the biological features of these neoplasms. We studied seven cases of BSCC of the oesophagus, five cases of ACC and seven cases of mucoepidermoid carcinoma. Squamous cell carcinoma and adenocarcinoma of the oesophagus and trachea were also studied for comparison. Among the cytokeratin subtypes examined, CK14, CK17 and CK19 immunoreactivity was detected in BSCC. ACC and mucoepidermoid carcinoma were immunopositive for CK8, CK14 and CK17 and for CK8, CK14, CK17 and CK19, respectively. These findings suggest that CK subtypes, especially CK8, CK14 and CK17, are useful in differentiating these malignancies. BSCC was more frequently associated with decreased E-cadherin and alpha-catenin immunoreactivity than ACC and mucoepidermoid carcinoma. Nuclear p53 immunoreactivity was detected more frequently in BSCC (5 out of 7) than in ACC (2 out of 5) and mucoepidermoid carcinoma (4 out of 7). There were no significant differences in p27 immunoreactivity among these carcinomas. Carcinoembryonic antigen (CEA) immunoreactivity was detected in mucoepidermoid carcinoma (2 out of 7), SCC (8 out of 11) and adenocarcinoma (9 out of 9), but it was not detected in BSCC (7) or ACC (5). Carbohydrate antigen 19-9 (CA19-9) immunoreactivity was detected only in mucoepidermoid carcinoma (4 out of 7) and adenocarcinoma, but not in BSCC, ACC, or SCC. These findings indicate that BSCC, ACC and mucoepidermoid carcinoma are distinct neoplasms arising in the upper aerodigestive tract. In addition, decreased expression of E-cadherin and alpha-catenin proteins and increased p53 expression in BSCC may be correlated with aggressive behaviour.
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PMID:Immunohistochemical study of basaloid squamous cell carcinoma, adenoid cystic and mucoepidermoid carcinoma in the upper aerodigestive tract. 1081 Apr 23

Similar to that of other herpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) lytic replication destroys the host cell, while the virus can persist in a latent state in synchrony with the host. During latency only a few genes are transcribed, and the question becomes one of what determines latent versus lytic gene expression. Here we undertake a detailed analysis of the latency-associated nuclear antigen (LANA [orf73]) promoter (LANAp). We characterized a minimal region that is necessary and sufficient to maintain high-level transcription in all tissues tested, including primary endothelial cells and B cells, which are the suspected natural host for KSHV. We show that in transient-transfection assays LANAp mimics the expression pattern observed for the authentic promoter in the context of the KSHV episome. Unlike other KSHV promoters tested thus far, LANAp is not affected by tetradecanoyl phorbol acetate or viral lytic cycle functions. It is, however, subject to control by LANA itself and cellular regulatory factors, such as p53. This is in contrast to the K14/vGCR (orf74) promoter, which overlaps LANAp and directs transcription on the opposite strand. We isolated a minimal cis-regulatory region sufficient for K14/vGCR promoter activity and show that it, too, mimics the regulation observed for the authentic viral promoter. In particular, we demonstrate that its activity is absolutely dependent on the immediate-early transactivator orf50, the KSHV homolog of the Epstein-Barr virus Rta transactivator.
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PMID:Differential regulation of the overlapping Kaposi's sarcoma-associated herpesvirus vGCR (orf74) and LANA (orf73) promoters. 1116 Jun 78


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