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)

One set of genes sufficient for transformation of primary human cells uses the combination of Ha-Ras-V12, the telomerase catalytic subunit hTERT, SV40 large tumor antigen (LT), and SV40 small tumor antigen (ST). Whereas SV40 LT inactivates the retinoblastoma protein and p53, the contribution of ST is poorly understood. The essential helper function of ST requires a functional interaction with protein phosphatase 2A (PP2A). Here we have identified changes in gene expression induced by ST and show that ST mediates these changes through both PP2A-dependent and PP2A-independent mechanisms. Knockdown of PP2A B56gamma subunit can substitute for ST expression to fully transform cells expressing LT, hTERT, and Ras-V12. We also identify those genes affected similarly in two cell lines that have been fully transformed from a common parental line by two alternative mechanisms, namely ST expression or PP2A B56gamma subunit knockdown. ST altered expression of genes involved in proliferation, apoptosis, integrin signaling, development, immune responses, and transcriptional regulation. ST reduced surface expression of MHC class I molecules, consistent with a need for SV40 to evade immune detection. ST expression enabled cell cycle progression in reduced serum and src phosphorylation in anchorage-independent media, whereas B56gamma knockdown required normal serum levels for these phenotypes. Inhibitors of integrin and src signaling prevented anchorage-independent growth of transformed cells, suggesting that integrin and src activation are key ST-mediated events in transformation. Our data support a model in which ST promotes survival through constitutive integrin signaling, src phosphorylation, and nuclear factor kappaB activation, while inhibiting cell-cell adhesion pathways.
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PMID:Signaling and transcriptional changes critical for transformation of human cells by simian virus 40 small tumor antigen or protein phosphatase 2A B56gamma knockdown. 1546 90

We compared the DNA-binding activity of transcription factors and gene expression patterns in BJ human diploid fibroblasts (HDFs) expressing or not telomerase (hTERT) in stress-induced premature senescence (SIPS). Senescent BJ cells were also studied. Hydrogen peroxide (H2O2)-induced SIPS modulated gene expression in both BJ and hTERT-BJ1 cells. Increased p21(WAF-1) mRNA level was amongst the common gene expression changes in BJ and hTERT-BJ1 cells induced by SIPS. Telomerase expression markedly changed gene expression in non-stressful conditions. Expression patterns of senescent BJ cells partially overlapped those of BJ and hTERT-BJ1 cells in SIPS. The basal levels of DNA-binding activity of NF-kappaB and phosphorylated ATF-2 were different in BJ and hTERT-BJ1 cells. Both cell lines displayed a higher DNA-binding activity of p53 and HIF-1 72 h after H2O2 exposure. Our results indicate that similar mechanisms involving p21(WAF-1) and probably p53 are at work in BJ and hTERT-BJ1 HDFs under H2O2-induced SIPS, suggesting that generalized DNA damage rather than telomere length/telomerase plays a crucial role in H2O2induced SIPS. We propose that H2O2-induced SIPS involves a rearrangement of proliferative and apoptotic pathways. The marked changes in gene expression induced by telomerase suggest that apart from immortalization of HDFs, telomerase also alters the normal cellular functions but does not protect against SIPS.
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PMID:Gene expression and regulation in H2O2-induced premature senescence of human foreskin fibroblasts expressing or not telomerase. 1548 61

Normal human diploid cells have a limited life span and undergo replicative senescence after various limited population doublings. Cells must pass the senescence barrier to become immortal. The exact mechanisms of immortalization are not clear, although inactivation of the RB pathway, and/or the p53 pathway and activation of telomerase has been shown to be necessary for immortalization of certain cell types with DNA viruses or hTERT. Methylation-associated inactivation of tumor suppressor genes plays an important role in tumor progression. To test if gene-specific methylation contributes to the immortalized and transformed phenotype, we analyzed the methylation status of 17 genes in normal cells immortalized with SV40, hTERT, Ad5, Ad12-SV40 or HPV-18. Some of these immortalized lines were progressively transformed and tumorigenic in nude mice. We observed gene-specific methylation in the in vitro immortalized and transformed cells. SV40 and HPV18 immortalization resulted in different methylation spectra. In SV40- and h-TERT-immortalized prostate epithelial cells, the most frequently methylated gene was RASSF1A, while in HPV18-immortalized cell lines, the RAR-beta2 gene was universally methylated. Immortalization with SV40 resulted in methylation of a greater number of genes than immortalization with HPV. Furthermore, in SV40-immortalized cell lines, methylation affected different genes in fibroblasts compared with epithelial cells, suggesting that different mechanisms may be used by SV40 to immortalize cell lines of different origins. In HPV18-immortalized and subsequently transformed cell lines, the most commonly methylated genes were hormone responsive genes, such as AR, ER-beta and RAR-beta2. In general, more genes were methylated in neoplastically-transformed cell lines than in only immortalized cell lines, indicating that accumulation of epigenetic abnormalities may contribute to oncogenesis.
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PMID:A methylation profile of in vitro immortalized human cell lines. 1558 50

In the wake of recent progress in understanding the genetic pathways involved in the development of brain tumors, a major goal is to correlate molecular data with clinical outcome, survival, and response to treatment modalities. This is of particular importance among the pediatric population. Reliable prognostic factors could potentially permit a tailoring of therapy in that only patients with the most aggressive tumors would receive the most intense treatments. A survey of publications about prognosis-related molecular features among pediatric brain tumors revealed 74 series, of which 46 presented statistically significant outcome-associated parameters as defined by a p value <0.05. Most investigations revealing significant prognosis-related features were performed on medulloblastomas (34 publications), followed by astrocytic tumors (6 publications) and ependymomas (5 publications). Promising approaches and molecular markers include gene expression profiles, DNA ploidy, loss of heterozygosity and chromosomal aberrations as detected by CGH and FISH (1q, 17p, 17q), as well as oncogenes/ tumor suppressor genes and their proteins (TP53, PTEN, c-erbB2, N-myc, c-myc), growth factor and hormonal receptors (PDGFRA, VEGF, EGFR, HER2, HER4, ErbB-2, hTERT, TrkC), cell cycle genes (p27) and cell adhesion molecules, as well as factors potentially related to therapeutic resistance (multi-drug resistance, DNA topoisomerase IIalpha, metallothionein, P-glycoprotein, tenascin). This review discusses the predictive potential of molecular markers for clinical outcome and their influence on therapeutic decision-making among children with brain tumors.
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PMID:Prognosis-related molecular markers in pediatric central nervous system tumors. 1562 58

Human fibroblast cells obtained from a normal individual and immortalized by introduction of the hTERT gene were irradiated with 0 to 5 Gy of acute high-dose-rate radiation (1.8 Gy/min) or chronic low-dose-rate radiation (0.3 mGy/min) in the G0 phase, and p53 activation was studied. After high-dose-rate irradiation, a dose-dependent induction of Ser15 phosphorylation was observed, whereas after low-dose-rate irradiation almost none was observed. Then we analyzed the focus formation of phosphorylated histone H2AX protein, which is closely correlated with the induction of double-strand breaks. High-dose-rate radiation induced a significant number of foci in a dose-dependent manner, whereas, low-dose-rate radiation could induce only a few foci even at the highest dose. These results strongly suggest that DNA damage induced by low-dose-rate radiation such as a double-strand break is efficiently repaired during chronic irradiation.
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PMID:No induction of p53 phosphorylation and few focus formation of phosphorylated H2AX suggest efficient repair of DNA damage during chronic low-dose-rate irradiation in human cells. 1563 61

The human ocular surface is covered by the conjunctival, corneal and limbal stratified epithelia. While conjunctival stem cells are distributed in bulbar and forniceal conjunctiva, corneal stem cells are segregated in the basal layer of the limbus, which is the transitional zone between the cornea and the bulbar conjunctiva. Keratinocyte stem and transient amplifying (TA) cells when isolated in culture give rise to holoclones and paraclones, respectively. Keratinocyte replicative senescence ensues when all holoclones have generated paraclones which express high levels of p16(INK4a). In the present study, we show that enforced telomerase activity induces the bypass of replicative senescence in limbal and conjunctival keratinocytes, without the inactivation of the p16(INK4a)/Rb pathway or the abrogation of p53 expression. hTERT-transduced limbal and conjunctival keratinocytes are capable to respond to both growth inhibitory and differentiation stimuli, since they undergo growth arrest in response to phorbol esters, and activate p53 upon DNA damage. Following a sustained PKC stimulation, occasional clones of p16(INK4a)-negative cells emerge and resume ability to proliferate. Telomerase activity, however, is unable to induce the bypass of senescence in corneal TA keratinocytes cultured under the same conditions. These data support the notion that telomere-dependent replicative senescence is a general property of all human somatic cells, including keratinocytes, and suggest that telomerase activity is sufficient to extend the lifespan only of keratinocytes endowed with high proliferative potentials (which include stem cells), but not of TA keratinocytes.
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PMID:Telomerase activity is sufficient to bypass replicative senescence in human limbal and conjunctival but not corneal keratinocytes. 1567 13

Reactivation of telomerase is a feature in many cancer cells. Telomerase activation inhibits telomere shortening, thereby preventing cell cycle arrest and apoptosis activated by shortened telomeres or chromosomal rearrangements. The tumor-suppressor gene product, p53, was previously shown to transcriptionally suppress the activation of the catalytic subunit of telomerase (hTERT). Here we have evaluated the role of p73 in hTERT regulation. We found that ectoptic expression of p73beta, in contrast to p73alpha or p53, in p53 null H1299 cells does not lead to suppression of hTERT transcription. However co-expression of p73alpha or p73beta together with p53 abolished p53-mediated hTERT suppression. This phenomenon was found to be dependent on the DNA binding ability of p73. We also show that p53-mediated suppression of hTERT transcription requires a minimum threshold level of p53, and p73 abrogates p53-mediated suppression by reducing p53 levels through the activation of HDM2. Moreover, p53-mediated hTERT suppression was not relieved by p73beta in cells depleted of HDM2 through small interfering RNA-mediated gene silencing. In addition, knockdown of HDM2 in MCF7 cells, which express moderately high levels of p73 and p53, resulted in the reduction of endogenous hTERT levels. Finally, knockdown of p73 in MCF7 cells resulted in increased p53 protein levels and a concomitant decrease in hTERT levels. Together, our data indicate a plausible way by which p73, through HDM2, can oppose p53 tumor suppressor function, thereby possibly contributing to tumorigenesis.
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PMID:Relief of p53-mediated telomerase suppression by p73. 1573 40

Telomerase activity is repressed in most human somatic tissues during differentiation processes but strongly up-regulated in most human tumors. Regulation of human telomerase activity primarily occurs at the level of transcriptional initiation of the TERT gene, which encodes the catalytic subunit of telomerase. We have generated a novel transgenic mouse model to study the regulation of the human TERT gene promoter in an in vivo system. For this purpose, we have cloned an 8.0-kbp human TERT promoter fragment in front of the bacterial lacZ reporter gene (hTERTp-lacZ), which encodes the beta-galactosidase enzyme. Expression of the reporter gene was monitored by reverse transcription-PCR analysis, 5-bromo-4-chloro-3-indolyl-beta-d-galactopyranoside staining of whole mount preparations, and histologic sections. We find that the activity of the human TERT promoter in most normal mouse tissues recapitulates the expression of the hTERT gene in normal human tissues and is under tighter control when compared with the endogenous mouse TERT gene expression. In testis, where highest lacZ expression was observed, the expression of the reporter gene was restricted to the spermatogonial stem cells and the spermatocytes. Intriguingly, we find increased levels of lacZ expression in mammary tumors of hTERTp-lacZ x p53(+/-) bitransgenic mouse mammary tumor model. Thus, this transgenic mouse model provides a suitable in vivo system to analyze the expression of the human TERT gene under physiologic conditions and during tumorigenesis.
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PMID:A novel transgenic mouse model reveals humanlike regulation of an 8-kbp human TERT gene promoter fragment in normal and tumor tissues. 1573 2

We have used cultured human mammary epithelial cells (HMEC) and breast tumor-derived lines to gain information on defects that occur during breast cancer progression. HMEC immortalized by a variety of agents (the chemical carcinogen benzo(a)pyrene, oncogenes c-myc and ZNF217, and/or dominant negative p53 genetic suppressor element GSE22) displayed marked upregulation (10-15 fold) of the telomere-binding protein, TRF2. Upregulation of TRF2 protein was apparently due to differences in post-transcriptional regulation, as mRNA levels remained comparable in finite lifespan and immortal HMEC. TRF2 protein was not upregulated by the oncogenic agents alone in the absence of immortalization, nor by expression of exogenously introduced hTERT genes. We found TRF2 levels to be at least twofold higher than in control cells in 11/15 breast tumor cell lines, suggesting that elevated TRF2 levels are a frequent occurrence during the transformation of breast tumor cells in vivo. The dispersed distribution of TRF2 throughout the nuclei in some immortalized and tumor-derived cells indicated that not all the TRF2 was associated with telomeres in these cells. The process responsible for accumulation of TRF2 in immortalized HMEC and breast tumor-derived cell lines may promote tumorigenesis by contributing to the cells' ability to maintain an indefinite lifespan.
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PMID:Accumulation and altered localization of telomere-associated protein TRF2 in immortally transformed and tumor-derived human breast cells. 1573 11

Epigenetic control provides a mechanism for the reversible silencing of telomerase expression that occurs as a natural consequence of differentiation. Significant overlap between indirect telomerase regulation pathways and cell cycle checkpoint pathways exist, suggesting that these discrete genetic elements (namely, p21, p53, and hTERT) synergistically cooperate to inhibit tumorigenesis. Mutations in these pathways have been known to contribute to cancer formation. However, the incorporation of epigenetic regulatory mechanisms provides another line of defense against these negative occurrences. These proteins are also implicated in the process of senescence, caused in eukaryotic cell lines by telomere shortening. Although the debate continues, there is significant evidence to classify the process of cellular senescence as an in vitro model for human aging. In addition, the study of stem cells gives information about the down-regulation of hTERT in the aging process. Diseases such as Werner S syndrome, ATM (ataxia telangiectasia mutated kinase), DKC (dyskeratosis congenita), and atherosclerosis have been linked to aberrant telomerase expression and other aging-related tissue malfunctions could be related to the presence of senescent cells changing the cellular microenvironment. Therefore, restoring telomerase activity as a putative therapeutic strategy necessitates further study to elucidate the intricacies linking genetic and epigenetic modulations of hTERT.
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PMID:Epigenetic control of telomerase and modes of telomere maintenance in aging and abnormal systems. 1576 67


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