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)

Prostate cancer and benign tumors of the prostate are the two most common neoplastic diseases in men in the United States, however, research on their causes and treatment has been slow because of the difficulty in obtaining fresh samples of human tissue and a lack of well characterized cell lines which exhibit growth and differentiation characteristics of normal prostatic epithelium. Non-neoplastic adult human prostatic epithelial cells from a white male donor were immortalized with human papillomavirus 18 which resulted in the establishment of the RWPE-1 cell line. Cells from the RWPE-1 cell line were further transformed by v-Ki-ras to establish the RWPE-2 cell line. The objectives of this study were to: (1) establish the prostatic epithelial origin and androgen responsiveness of RWPE-1 and RWPE-2 cell lines; (2) examine their response to growth factors; and (3) establish the malignant characteristics of the RWPE-2 cell line. Immunoperoxidase staining showed that both RWPE-1 and RWPE-2 cells express cytokeratins 8 and 18, which are characteristic of luminal prostatic epithelial cells, but they also coexpress basal cell cytokeratins. These cell lines show growth stimulation and prostate specific antigen (PSA) and androgen receptor (AR) expression in response to the synthetic androgen mibolerone, which establishes their prostatic epithelial origin. Both cell lines also show a dose-dependent growth stimulation by EGF and bFGF and growth inhibition when exposed to TGF-beta, however, the transformed RWPE-2 cells are less responsive. RWPE-1 cells neither grow in agar nor form tumors when injected into nude mice with or without Matrigel. However, RWPE-2 cells form colonies in agar and tumors in nude mice. In the in vitro invasion assay, RWPE-1 cells are not invasive whereas RWPE-2 cells are invasive. Nuclear expression of p53 and Rb proteins was heterogeneous but detectable by immunostaining in both cell lines. The RWPE-1 cells, which show many normal cell characteristics, and the malignant RWPE-2 cells, provide useful cell culture models for studies on prostate growth regulation and carcinogenesis.
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PMID:Androgen responsive adult human prostatic epithelial cell lines immortalized by human papillomavirus 18. 921 5

Transformed fibroblast from p53 null/null mice were tested for their sensitivity to intercellular induction of apoptosis by TGF-beta-treated nontransformed cells. They were found to be as sensitive as p53-positive transformed cells. Based on morphological criteria, detection of chromatin condensation and DNA strand breaks, death of p53-negative transformed cells was due to apoptosis. p53-negative nontransformed cells were as efficient in the induction of apoptosis in transformed cells as p53-positive nontransformed cells. These data show that intercellular induction of apoptosis in transformed cells does not depend on functional p53. Therefore it may be assumed that mutations of p53 or modulation of its concentration are without relevance for this particular aspect of control of oncogenesis.
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PMID:Intercellular induction of apoptosis in transformed cells does not depend on p53. 926 65

The high risk human papillomaviruses (HPVs) are associated etiologically with the majority of human cervical carcinomas. These HPVs encode two viral oncoproteins, E6 and E7, which are expressed consistently in cervical cancers. The function of these viral oncoproteins during a productive infection is to ensure viral replication in cells that have normally withdrawn from the cell division cycle and are committed to terminal differentiation. Expression of the E7 oncoprotein has been shown to lead to the abrogation of various negative growth regulatory signals, including a p53-mediated G1 growth arrest, TGFbeta-mediated growth inhibition, and quiescence of suprabasal keratinocytes. Here we describe a novel mechanism by which E7 can uncouple cellular proliferation and differentiation. In contrast to normal, differentiating keratinocytes, HPV-16 E7-expressing keratinocytes show delayed cellular differentiation and elevated cdk2 kinase activity despite high levels of p21(Cip1) and association of p21(Cip1) with cdk2. We show that the HPV E7 protein can interact with p21(Cip1) and abrogate p21(Cip1)-mediated inhibition of cyclin A and E-associated kinase activities. Based on these findings, we propose that this capacity of the HPV E7 oncoprotein to overcome p21(Cip1)-mediated inhibition of cdk2 activity during keratinocyte differentiation contributes to the ability of E7 to allow for cellular DNA synthesis in differentiated keratinocytes.
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PMID:The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21Cip1-mediated inhibition of cdk2. 928 49

The expression of the tumor suppressor/oncoprotein p53 has been investigated in normal human placental villous trophoblast, in vitro propagated invasive extravillous trophoblast, SV40 tumor antigen (Tag)-immortalized extravillous trophoblast, human cytomegalovirus (hCMV)-infected syncytiotrophoblast and malignant trophoblast (choriocarcinoma) cell lines (JAR, JEG-3 and BeWo) using quantitative enzyme-linked immunosorbent assay (ELISA) and Western immunoblot methods using monoclonal antibodies specific for wild-type and mutant p53. The normal villous and extravillous trophoblast cells expressed low levels of the wild-type p53 protein, whereas normal terminally differentiated multinucleated syncytiotrophoblast cells, as well as hCMV-infected syncytiotrophoblast, showed a higher expression of the wild-type p53 protein. SV40 Tag-immortalized invasive trophoblast cells also showed a high expression of the wild-type p53 protein which remained complexed with the Tag protein. All the choriocarcinoma cell lines over expressed the mutant form of the p53 protein. The increased expression of p53 protein in the SV40 Tag-immortalized invasive trophoblast and choriocarcinoma cells paralleled with increased expression of the mouse double minute 2 (mdm2) oncogenic protein. Transforming growth factor (TGF)-beta inhibited proliferation of normal extravillous trophoblast cells. The antiproliferative effects of TGF-beta were reduced in SV40 Tag-immortalized cells and non-detectable in choriocarcinoma cell lines JAR, BeWo and JEG-3. The inactivation of p53 owing to complexing with Tag in the immortalized premalignant trophoblast and p53 mutation in the malignant trophoblast may be responsible for their aberrant proliferation and refractoriness to antiproliferative effects of TGF-beta observed in these cells as compared to the normal trophoblast. These results may suggest the role of p53 protein in trophoblast differentiation, transformation and tumorigenesis.
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PMID:Altered expression of the tumor suppressor/oncoprotein p53 in SV40 Tag-transformed human placental trophoblast and malignant trophoblast cell lines. 936 7

The mRNA expressions of various growth regulatory molecules in single human anagen hair follicles were analysed by reverse transcription and polymerase chain reaction. Approximately 370 hair follicles were isolated from 20 normal individuals, and 0.90 +/- 0.34 microgram (mean +/- SD) total RNA was extracted per whole hair follicle. The mRNAs of fibroblast growth factor (FGF)-1, FGF-2, FGF-5, FGF-7, transforming growth factor (TGF)-alpha, TGF-beta 1, hepatocyte growth factor, insulin-like growth factor (IGF)-I, tumour suppressor gene p53 and high sulphur protein were detected in most or all of the examined hair follicles per target gene. In contrast, none of the mRNAs of FGF-3, FGF-4, FGF-6, FGF-9 and IGF-II was detected, and those of TGF-beta 2 and TGF-beta 3 were detected in only a limited number of the examined hair follicles. Among cyclin-dependent kinase inhibitors, the mRNAs of p21waf1/cip1 and p27kip1 were expressed in almost all the hair follicles, while those of p15INK4B and p16INK4A were not detected. These results suggest that both positive and negative factors for the proliferation and differentiation of follicular epithelial cells coexist in a human anagen hair follicle.
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PMID:Genes for a range of growth factors and cyclin-dependent kinase inhibitors are expressed by isolated human hair follicles. 941 26

Characteristics of human hepatoma cell lines with the wild-type p53 were compared with those of human hepatoma cell lines with the mutant-type p53. The p21 protein located downstream of p53 was expressed in cell lines with the wild-type p53 but was not expressed in cell lines with the mutant-type p53. As to other tumor suppressor genes such as p16 and p27, there was no difference in their expression between both types of cell lines. In addition, no marked difference was observed in the activities of CDK2 and CDK4 between cell lines with the wild-type and the mutant-type p53. Phosphorylated Rb protein was detected in all cell lines except the HLE line, indicating that this cell line may have a deletion of and/or a mutation of the Rb gene. These results indicate that abnormalities of tumor suppressor genes other than p53, p16, p27, and Rb may be involved in hepatocarcinogenesis. The population doubling time of the wild-type p53 cells was significantly longer than that of the mutant p53 cells. Neither type of cell line showed a specific chromosome distribution which would indicate karyotype instability. The cell lines expressing the wild-type p53 produced tumors at lower frequency than those with the mutant p53 gene. Although there was no significant difference in effects of TGF-beta 1, EGF, cholera toxin, and db-cAMP on cell growth between the two types of cells, all three cell lines with the wild-type p53 were resistant to cytotoxicity of TNF-alpha, while two of the three with the mutant p53 were very sensitive to its cytotoxic effects.
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PMID:Comparison of cellular characteristics between human hepatoma cell lines with wild-type p53 and those with mutant-type p53 gene. 943 73

Cancer in adenomas are thought to be an excellent model of colorectal carcinogenesis based on the adenoma-carcinoma sequence. We searched for alterations in the APC mutation cluster region, the whole coding regions of TGF-beta type II receptor (RII) and beta-catenin exon 3 in 16 cases of cancer in adenomas of the colon. Overexpression of the p53 protein was also analyzed. Nine of the 16 cases showed APC mutations in both the adenoma and cancer regions. Loss of heterozygosity in APC was found in one cancer in adenoma that had no mutation. p53 overexpression was detected in one adenoma and 10 cancerous regions, most of which also exhibited APC alterations. Two cases showed a missense mutation at codon 191 or loss of heterozygosity in TGF-beta RII in both the adenoma and cancer. Our data support the hypothesis that alterations of APC and p53 are responsible for most of the adenoma-carcinoma pathway, rather than TGF-beta RII alterations.
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PMID:Genetic alterations are frequent in APC but rare in the TGF-beta type II receptor gene in cancer in adenomas of the colon. 956 1

Ampullary carcinomas are relatively rare cancers of which very little is known in terms of carcinogenetic mechanisms at the molecular level. Genetic instability caused by mutations of mismatch-repair genes has been demonstrated to be responsible for hereditary non-polyposis colorectal cancers and a sub-set of sporadic colorectal cancers. In some of those tumors showing genetic instability, the transforming-growth-factor-beta(TGF-beta)-receptor-II gene has been found to be mutated in repetitive sequences and considered to be a target of replication error. We studied the role of genetic instability and associated TGF-beta-receptor-II-gene mutations in a series of 18 sporadic cases by analyzing 5 microsatellite loci (D2S123, D3S1029, D5S409, TP53 and BAT26) and by sequencing a poly-A repeat (nucleotides 709-718) in the TGF-beta-receptor-II gene. Microsatellite instability was observed in 4 (22.2%) and gene mutations in 14 (77.8%) cases. These data indicate that the TGF-beta-receptor-II gene might be a preferential target of genetic instability whose alteration might be specifically advantageous and constitute a common step in the development of ampullary carcinomas.
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PMID:Genetic instability and mutation of the TGF-beta-receptor-II gene in ampullary carcinomas. 957 79

In recent two years, a group of protein factors have been found to combine with the cyclin-dependent kinases (CDKs) and block the activation of cyclin/CDK complexes. They are named CDK inhibitors (CKIs) as p21, p16, p15, p27 and CDI1. The p21 and p27 have certain homology and can inhibit the activity of multiple CDKs; p16 and p15 have higher homology and can specifically combine with CDK4 and CDK6; and the combination specificity of CDI1 needs further research. The expression of p21 is regulated positively by p53. TGF-beta can upregulate the expression of p15 and the inhibitory activity of p27. The above findings demonstrate that CKIs are not only the regulators of CDKs' activity but also the direct linkers between cancer inhibitors and cell-cycle regulation.
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PMID:[Cyclin-dependent kinase inhibitors in mammal cells]. 959 31

p21waf1/cip1 encodes a cyclin-dependent kinase inhibitor that is transcriptionally activated by the p53 tumor suppressor gene, transforming growth factor beta 1 (TGF-beta 1), AP2, and other pathways. Because p21waf1/cip1, p53, and TGF-beta 1 all regulate apoptosis and the cell cycle, we tested the hypothesis that their relative protein levels would correlate with biological features including the survival of non-small cell lung cancer (NSCLC) patients. We conducted an immunohistochemical analysis of p21waf1/cip1 and TGF-beta 1 and identified four patient groups with distinct survival outcomes. Concordant p21waf1/cip1 and TGF-beta 1 expression (i.e., either high p21waf1/cip1 and high TGF-beta 1 expression or low p21waf1/cip1 and low TGF-beta 1 expression) predicted 70% disease-free survival at 2000 days of follow-up. Discordant p21waf1/cip1 and TGF-beta 1 expression (i.e., either high p21waf1/cip1 and low TGF-beta 1 expression or low p21waf1/cip1 and high TGF-beta 1 expression) predicted 35% disease-free survival (P = 0.0003; log-rank test). These survival relationships were not attributable to differences in grade, stage, or p53 status. Although current models do not fully explain these complex interactions, most of these data fit a paradigm whereby TGF-beta 1 regulation determines NSCLC survival. In addition to the survival correlation, we found that high p21waf1/cip1 protein expression correlated with high tumor grade (P = 0.014). There is little evidence that p21waf1/cip1 protein levels accurately predict p53 mutation status in NSCLC; specifically, 20 of 48 (42%) tumors with p53 mutations contained high levels of p21waf1/cip1 protein. These findings indicate that p21waf1/cip1 immunohistochemical analysis may provide useful information concerning the biological properties of NSCLC.
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PMID:p21waf1/cip1 and transforming growth factor beta 1 protein expression correlate with survival in non-small cell lung cancer. 962 68


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