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

The E6/E7 oncoproteins of human papillomavirus (HPV) types 16 and 18 are responsible for the efficient immortalization of human genital keratinocytes and we have recently reported that such immortalized cells display alterations in the expression of cyclin A, cyclin B, and cdc-2. To determine whether these alterations were the consequence of E6/E7 protein expression or whether they resulted from the process of cellular immortalization, we multiply-infected primary genital keratinocytes with a retrovirus expressing the HPV-18 E6/E7 genes and examined the cells for acute, pre-immortalization changes in several critical cell growth regulatory proteins including cyclin A, cyclin B, cdc-2, p53 and c-myc. In addition, we simultaneously evaluated the expression of the E6/E7, bcl-2 and involucrin genes to determine whether there were accompanying alterations in the expression of viral genes or in cellular genes related to cell apoptosis and the state of keratinocyte differentiation. The cell cycle regulating proteins (cyclin A, cyclin B, cdc-2 and p53) change significantly within days after retroviral infection. Cyclin B and cdc-2 increase over 4-fold by three passages and remain relatively constant thereafter through passage 21, whereas the levels of p53 protein decrease 25% by passage three. Increases in the expression of cyclin A, cyclin B and cdc-2, and decreases in p53 are therefore among the earliest observable changes in cell regulatory proteins following E6/E7 gene expression and may be important contributors to the development of cell immortalization. The expressions of viral E6/E7 genes, c-myc, bcl-2 and involucrin exhibit progressive changes with increased passage numbers until passage 21, presumably reflecting the selective outgrowth of immortalized cells.
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PMID:The human papillomavirus E6/E7 genes induce discordant changes in the expression of cell growth regulatory proteins. 870 40

Malignant rhabdoid tumor of the kidney (RTK) is a rare renal sarcoma of childhood. Its histogenesis is unclear, and it is highly resistant to multimodality therapy. To elucidate the origin and the oncogenetic potential of RTK, we investigated the characteristics of 2 newly established RTK cell lines, SWT-1 and SWT-2. Both cell lines were verified to be RTK, since they did not exhibit contact inhibition and exhibited intermediate filaments, a specific marker for RTK. These cells possess the characteristics of mesenchymal cells based on their positive reactions with anti-vimentin and anti-laminin antibodies and their negative reactions with anti-keratin and anti-desmin antibodies. The karyotype of SWT-1 was 46,XX and that of SWT-2 was 46,XX,del(11)(pter-p13::p12-qter). Since 11p13 is the location of the WT-1 tumor-suppressor gene, and del(11p13) is associated with the aniridia-Wilms'-tumor syndrome, these findings link RTK with Wilms' tumor. While SWT-1 was negative for the tumor markers examined, SWT-2 released tissue polypeptide antigen into the culture supernatant. No rearrangement or amplification of the myc and ras oncogenes or of the p53 tumor-suppressor gene were detected. Wild-type RB protein and cyclin A were expressed in both cells. Our data suggest that these 2 cell lines may be useful in identifying the oncogenetic pattern of RTK.
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PMID:Establishment and characterization of two cultured cell lines derived from malignant rhabdoid tumors of the kidney. 876 May 91

Differentially regulated expression of activators and inhibitors of cyclin-dependent kinases (cdks) modulate cell cycle progression. In normal fibroblasts, these complexes consist of the cdk inhibitor p21WAF1/PCNA/G1 cyclin/cdk. We now show that bromodeoxyuridine (BrdUrd), a thymidine analogue and radiation sensitizer, inhibits growth and activity of cyclin A-cdk2 kinase in metastatic C8161 and nonmetastatic neo 6.3/C8161 human melanoma cells. Inhibition is not due to altered levels of cyclin D or catalytic cdk2 but involves a decrease in cyclin A and proliferating cell nuclear antigen, paralleled by higher levels of p21WAF1 without increases in p53. In contrast to serum starvation, which prevents accumulation of cyclins A and D in normal fibroblasts, such treatment did not down-regulate either cyclin in these melanoma cells, implying an aberrant control for G1 cyclins in these tumor cells. However, cyclin A was decreased by BrdUrd, suggesting that this pyrimidine analogue arrests melanoma cells at a G1 transition point, unlike that of serum starvation. This is the first report indicating that the antitumor therapeutic action of BrdUrd may be mediated by a p53-independent reciprocal effect on activators and inhibitors of cdk kinases.
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PMID:p53-independent increase in p21WAF1 and reciprocal down-regulation of cyclin A and proliferating cell nuclear antigen in bromodeoxyuridine-mediated growth arrest of human melanoma cells. 882 3

In this study, we analyze effects of IFN-gamma on the proliferation of normal human mammary epithelial cells (MECs) and several mammary carcinoma cell lines. We demonstrate that IFN-gamma blocks the proliferation of MECs in a time- and concentration-dependent manner. This growth arrest is irreversible and occurs at a specific stage in the G1 phase of the cell cycle. IFN-gamma caused a rapid (within 12-24 h) down-regulation of cyclin A, c-myc, and cdc2 proteins, as well as a disappearance of hyperphosphorylated forms of the retinoblastoma family proteins, Rb and p130. The synthesis of several other growth control proteins, p53, p21/Waf1, and proliferating cell nuclear antigen, was down-regulated between 24 and 48 h. In MECs synchronized by epidermal growth factor deprivation and released for cell cycle traverse by re-addition of epidermal growth factor to the medium, IFN-gamma was able to block DNA synthesis only if added in the first 6 to 7 h after epidermal growth factor. The block in Rb phosphorylation and cyclin A expression was coordinately regulated during the same narrow window of G1. Several mammary carcinoma cell lines demonstrated resistance to the growth-inhibitory effects of IFN-gamma and did not exhibit down-regulation of cdc2 and cyclin A expression or a change in hyperphosphorylation of Rb when treated with IFN-gamma. Initial studies suggest, in some carcinoma cell lines, that resistance to IFN-gamma may be caused by defects in the IFN-gamma signal transduction pathway (measured by expression of the IFN-gamma-responsive gene GBP), while resistance in others may be due to defects in cell cycle regulatory proteins that are the targets of IFN-gamma action.
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PMID:Gamma-interferon induces an irreversible growth arrest in mid-G1 in mammary epithelial cells which correlates with a block in hyperphosphorylation of retinoblastoma. 883 59

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

The cyclin-dependent kinase (Cdk) inhibitor p21Waf1/Cip1/Sdi1, important for p53-dependent cell cycle control, mediates G1/S arrest through inhibition of Cdks and possibly through inhibition of DNA replication. Cdk inhibition requires a sequence of approximately 60 amino acids within the p21 NH2 terminus. We show, using proteolytic mapping, circular dichroism spectropolarimetry, and nuclear magnetic resonance spectroscopy, that p21 and NH2-terminal fragments that are active as Cdk inhibitors lack stable secondary or tertiary structure in the free solution state. In sharp contrast to the disordered free state, however, the p21 NH2 terminus adopts an ordered stable conformation when bound to Cdk2, as shown directly by NMR spectroscopy. We have, thus, identified a striking disorder-order transition for p21 upon binding to one of its biological targets, Cdk2. This structural transition has profound implications in light of the ability of p21 to bind and inhibit a diverse family of cyclin-Cdk complexes, including cyclin A-Cdk2, cyclin E-Cdk2, and cyclin D-Cdk4. Our findings suggest that the flexibility, or disorder, of free p21 is associated with binding diversity and offer insights into the role for structural disorder in mediating binding specificity in biological systems. Further, these observations challenge the generally accepted view of proteins that stable secondary and tertiary structure are prerequisites for biological activity and suggest that a broader view of protein structure should be considered in the context of structure-activity relationships.
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PMID:Structural studies of p21Waf1/Cip1/Sdi1 in the free and Cdk2-bound state: conformational disorder mediates binding diversity. 887 65

We have analyzed the regulation of subcellular compartmentation of mutant and wild-type (WT) p53 proteins as a function of the cell cycle using immunofluorescence microscopy and referring to different markers of position in the cell cycle in different human cells expressing either mutated (KHOS-240, A 431, and T47-D cells) or WT (WI 38 and MCF-7 cells) p53. The mutant p53 proteins present in the KHOS-240, A 431, and T47-D tumor-derived cell lines enter very rapidly in the nucleus in early postmitotic cells before the chromosomes have fully decondensed; they continue accumulating in this location without any obvious cytoplasmic retention throughout the cell cycle until prophase. Such behavior is similar to that observed for the WT p53 associating with SV40 large T antigen in human WI 38 cells transformed by SV40, but it is in contrast to the behavior of the WT p53 protein present in both the untransformed WI 38 and the tumor-derived MCF-7 cells. In these latter systems, the highest nuclear concentrations of the WT protein are always found in G1 cells that still fail to exhibit a high rate of nuclear cyclin A; past the G1-S transition, the nuclear level of WT p53 tends to decrease, possibly to the benefit of cytoplasmic expression, whereas that of cyclin A concomitantly increases, suggesting that the nuclear accumulation of WT p53 becomes restricted during the phase of DNA replication. As for Saos-2 cells stably transfected with the temperature-sensitive p53Ala-143 mutant, they become arrested before the G1-S transition with a heavy pool of nuclear p53 at 32.5 degrees C, the temperature at which the transcriptional activity of p53Ala-143 is restored. All these data are compatible with the presently acknowledged primary role for WT p53, which would be to brake transit through the G1-S border possibly by directly transactivating the p21cip1 protein.
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PMID:Cell cycle-dependent regulation of nuclear p53 traffic occurs in one subclass of human tumor cells and in untransformed cells. 887 2

The tumor suppressor gene p53, implicated in diverse types of human tumors, functions both as a gene-specific transcription factor as well as a specific inhibitor of the transcription of certain genes. The two physiological outcomes of re-expression of wild type p53 in tumor cells, not expressing wild type p53, are G1 arrest and apoptosis. The mechanism of G1 arrest by p53 is much better documented than its ability to trigger apoptosis. P53 as a transcription factor induces the expression of p21WAF1/CIP1/Sdi1, an inhibitor of the cyclin dependent kinases (CDKs)2, 3, 4 and 6. Thus, a G1 arrest can result simply by the p53 induced expression of p21WAF1/CIP1/Sdi1. Amongst the other genes presently characterized to be regulated by p53 are BAX, a homologue of the BCL-2 gene. Bax does not trigger apoptosis, but simply accelerates the rate at which apoptosis proceeds54. P53 also down regulates the expression of cyclin A, providing a secondary break on cell cycle progression into the through the S phase.
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PMID:The role of p53 in cell cycle regulation. 888 Aug 67

In vitro cell transformation is a valuable approach for studying the mechanisms of multistep carcinogenesis of human cells. Since immortalization is an essential step for in vitro neoplastic transformation of human cells, this study addresses the question of whether mutant p53 contributes to the immortalization process of human cells. The mutant p53 gene (mp53: codon273Arg-His) was introduced into normal human fibroblasts (OUMS-24 line) and a G418-resistant clone, OUMS-24/P6 line, was obtained. This clone showed an extended life span and chromosome abnormalities, but senesced at the 79th population doubling level (PDL). When these cells were subjected to intermittent X-ray treatment, they became an immortalized cell line (OUMS-24/P6X). Although these immortalized cells showed chromosome abnormalities, they were not tumorigenic. On the other hand, normal OUMS-24 cells into which mp53 had not been introduced were not immortalized by the same X-ray treatment. These results indicate that introduction and expression of mp53 alone were not sufficient for immortalization of human cells, and that mutations of the remaining wild-type p53 or other genes may have been necessary for immortalization. In fact, no expression of the wild-type p53 was detected in the immortalized cells by RT-PCR. Expression of p21, which is located downstream of p53, was remarkably reduced in the immortalized cells, resulting in an increase in cdk2 and cdc2 kinase activity. These findings indicate that the p53-p21 cascade may play some role in the immortalization of human cells. On the other hand, there was no significant difference in expression of proteins such as Rb, p16, cdk4, cdk6, cyclin A and cyclin D1 between the normal and immortalized human fibroblasts.
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PMID:Transformation of normal human fibroblasts into immortalized cells with the mutant p53 gene and X-rays. 898 2

The major transforming protein of human papillomaviruses (HPVs) is encoded by the E7 gene. This protein cooperates with activated oncogenes to transform primary rodent cells and with the viral E6 gene to immortalize primary human keratinocytes. Numerous cellular targets of HPV E7 have now been identified including pRb, p107, cyclin A, TATA box binding protein (TBP), and members of the AP-1 transcription factor family. As with Adenovirus E1a, many of these interactions are important for the ability of E7 to transform cells. Recent studies have demonstrated that Adenovirus E1a can also inhibit the transcriptional activity of the cellular tumor suppressor protein, p53. We have performed a series of analyses to determine whether HPV E7 proteins share this characteristic. We show that HPV E7 proteins derived from both benign and tumor-associated HPV types are able to inhibit p53 transcriptional activity. Mutational analysis of the HPV-16 E7 protein reveals that a key domain involved in mediating this activity is the casein kinase II (CKII) recognition site, which has been shown to modulate E7 binding to TBP. We further show that E7 does not bind to p53 directly, but will do so in the presence of exogenously added TBP and that this binding is increased following CKII phosphorylation. These results suggest that the E7-TBP interaction may be responsible for inhibiting p53 transcriptional activity.
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PMID:Repression of p53 transcriptional activity by the HPV E7 proteins. 900 83


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