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)

Three sources of fetal bovine serum (FBS) were fractionated by ammonium sulfate precipitation and by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), transferred to Immobilon-P membranes, immunoblotted with a panel of transcription factor antibodies, and detected by enhanced chemiluminescence. Nine transcription factors were detected--ATF-2, SRE-ZBP, GATA-2, TFIID, Ets-1/Ets-2, E2F-1, Oct-2, p53, and AP-2; four transcription factors were not detected--Myo D, CREB, Sp2, and Wilms' tumor. The results indicated the presence of varying amounts of several transcription factors in three commercial sources and may represent heretofore unrecognized factors influencing cell culture.
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PMID:The presence of transcription factors in fetal bovine sera. 954 56

Compared with vascular smooth muscle cells (VSMCs) from normal vessels, VSMCs from human atherosclerotic plaques proliferate more slowly, undergo earlier senescence, and demonstrate higher levels of apoptosis in culture. The tumor suppressor genes p105RB (retinoblastoma, acting through the E2F transcription factor family) and p53 regulate cell proliferation, cell senescence, and apoptosis in many cell types. We have therefore determined whether these stable growth properties of plaque VSMCs reflect altered activity of RB and/or p53. VSMCs were derived from coronary atherectomies or from normal coronary arteries from transplant recipients. Compared with normal VSMCs, plaque VSMCs showed a higher ratio of the active (hypophosphorylated) to the inactive (phosphorylated) form of RB and a lower level of E2F transcriptional activity. Cells were stably transfected with retrovirus constructs that inhibited RB or p53 alone or in combination. Suppression of RB alone increased rates of cell proliferation and apoptosis and inhibited cell senescence in normal VSMCs. Suppression of p53 and RB together had similar effects but, additionally, resulted in immortalization of normal VSMC cultures. In contrast, inhibition of RB binding to E2F or ectopic expression of E2F-1 in plaque VSMCs induced massive apoptosis, which required suppression of p53 to rescue cells. Suppression of RB and p53 together increased cell proliferation and delayed senescence but failed to immortalize plaque VSMCs. Inhibition of p53 alone had minimal effects on plaque VSMCs but increased the lifespan of normal VSMCs. We conclude that human plaque VSMCs have slower rates of cell proliferation and earlier senescence than do cells from normal vessels because of a defect in phosphorylation of RB. Furthermore, both disruption of RB/E2F and inhibition of p53 are required for plaque VSMCs to proliferate without apoptosis. This observation may explain the relatively low level of cell proliferation and high level of apoptosis seen in VSMCs in human atherosclerotic plaques.
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PMID:Cooperative interactions between RB and p53 regulate cell proliferation, cell senescence, and apoptosis in human vascular smooth muscle cells from atherosclerotic plaques. 954 79

Progression through the cell cycle is controlled by the induction of cyclins and the activation of cognate cyclin-dependent kinases. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovastatin induces growth arrest and cell death in certain cancer cell types. We have pursued the mechanism of growth arrest in PC-3-M cells, a p53-null human prostate carcinoma cell line. Lovastatin treatment increased protein and mRNA levels of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1), increased binding of p21 with Cdk2, markedly inhibited cyclin E- and Cdk2-associated phosphorylation of histone H1 or GST-retinoblastoma protein, enhanced binding of the retinoblastoma protein to the transcription factor E2F-1 in vivo, and induced the activation of a p21 promoter reporter construct. By using p21 promoter deletion constructs, the lovastatin-responsive element was mapped to a region between -93 and -64 relative to the transcription start site. Promoter mutation analysis indicated that the lovastatin-responsive site coincided with the previously identified transforming growth factor-beta-responsive element. These data indicate that in human prostate carcinoma cells an inhibitor of the HMG-CoA reductase pathway can circumvent the loss of wild-type p53 function and induce critical downstream regulatory events leading to transcriptional activation of p21.
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PMID:Inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway induces p53-independent transcriptional regulation of p21(WAF1/CIP1) in human prostate carcinoma cells. 955 23

The transfer of apoptosis genes to tumors is one of the most promising strategies for cancer gene therapy. We have shown that massive apoptosis occurs when wild-type p53 expression is induced in glioma cells carrying a p53 gene mutation. However, adenovirus-mediated p53 gene transfer is ineffective in causing apoptosis in glioma cells that retain a wild-type p53 genotype. We evaluated the effect of E2F-1 overexpression on the growth of gliomas in vitro and in vivo. In the in vitro study, the adenovirus-mediated transfer of exogenous E2F-1 protein precipitated generalized apoptosis in gliomas. The treatment with Ad5CMV-E2F-1 of nude mice carrying subcutaneous gliomas arrested tumor growth. Our results indicate that E2F-1 has anti-glioma activity in vitro and in vivo.
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PMID:Overexpression of E2F-1 in glioma triggers apoptosis and suppresses tumor growth in vitro and in vivo. 962 77

p202 is an interferon (IFN)-inducible, primarily nuclear, phosphoprotein (52-kDa) whose overexpression in transfected cells inhibits colony formation. p202 binds to the retinoblastoma tumor suppressor protein and two other members of the pocket family proteins (p107 and p130). Moreover, overexpression of p202 in transfected cells inhibits the transcriptional activity of E2Fs (E2F-1/DP-1 and E2F-4/DP-1), p53, AP-1 c-Fos and c-Jun, NF-kappaB p50 and p65. Here we demonstrate that inhibition of endogenous p202 production in murine AKR-2B fibroblasts did not result in an increase in cell proliferation. Instead, these cells exhibited increased susceptibility to apoptosis in response to decrease in serum concentrations in the growth medium. These observations are consistent with the notion that normal levels of p202 may be needed for the regulation of cell proliferation.
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PMID:p202 prevents apoptosis in murine AKR-2B fibroblasts. 964 35

Recent methodological developments allow expression measurement of many genes simultaneously, thereby revealing patterns of gene expression that can be related to phenotype. We hypothesized that through the use of such methods we could identify patterns of gene expression associated with the malignant phenotype in human bronchial epithelial cells (BEC). To test this hypothesis, a recently developed quantitative reverse transcriptase polymerase chain reaction method was used to assess simultaneously expression of 15 genes mechanistically associated with cell-cycle control (c-myc, E2F-1, p21, rb, PCNA, cyclin D2, cyclin D3, cyclin E, cdc2, CDK2, CDK4, mad, max p21, max p22, and p53) in normal cell cultures from five individuals and in nine different malignant BEC lines. Relative to the mean expression levels in cultured normal cell populations, expression of c-myc, E2F-1, PCNA, cyclin E, and CDK4 messenger RNA (mRNA) were significantly increased and expression of p21 and p53 mRNA were significantly decreased in one or two, but not all three subtypes (squamous, adenocarcinoma and small cell) of carcinoma cell lines evaluated. No single cell-cycle control gene discriminated all three subtypes from normal cell populations. In contrast, the gene expression index c-myc x E2F-1/p21 separated all carcinoma cell lines from all normal cell populations initially evaluated. This malignancy index was validated in an additional three cultured normal BEC and three carcinoma cell lines, as well as three pairs of matched primary normal bronchial epithelial and primary bronchogenic carcinoma samples, and three pairs of matched primary normal lung parenchyma and primary bronchogenic carcinoma tissue. Again, the c-myc x E2F-1/ p21 index successfully discriminated all cultured and primary normal from malignant samples and thereby had a predictive value of 1 (no false positives and no false negatives). We hypothesize that because of functional mutations in cell-cycle regulatory genes (e.g., p53 and/or rb), cells lose the ability to maintain a pattern of gene expression mechanistically associated with normal, division-limited homeostatic equilibrium. Because the c-myc x E2F-1/p21 gene expression index has high specificity for malignant tissue, it will allow confirmation that there is a significant amount of tumor tissue present in small (e.g., fine-needle) biopsy specimens prior to evaluating them for expression of other genes, such as those involved in chemoresistance or radioresistance. In addition, the goal of most gene therapy efforts is to alter levels of gene expression quantitatively. This index and others derived in a similar manner may better define potential gene therapy targets as well as response of targeted genes to therapy.
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PMID:The gene expression index c-myc x E2F-1/p21 is highly predictive of malignant phenotype in human bronchial epithelial cells. 965 Nov 76

Both E2F and p53 are sequence specific transcription factors that regulate early cell cycle progression. The pathway of control mediated through E2F governs the transition from G1 into S phase whereas p53 in response to genotoxic stress can facilitate cell cycle arrest or apoptosis. The mechanisms which influence the outcome of p53 induction are not clear, although transcription of the p53 target gene, encoding the cdk-inhibitor p21(Waf1/Cip1), correlates with p53-mediated cell cycle arrest. Here using a combination of biochemical and functional assays we identify p300 as a co-activator required for p53-dependent transcriptional activation of Waf1/Cip1. Furthermore, we show that the cdk-inhibitor p21(Waf1/Cip1) autoregulates in a positive fashion transcription through modulating the activity of the p53/p300 complex, whilst negatively regulating the activity of E2F by preventing cdk-dependent phosphorylation of pRb. Consistent with a role for p21(Waf1/Cip1) in the autoregulation of p53-dependent transcription, p300 augments the ability of p53 to cause G1 arrest and, conversely, cells undergoing p53-dependent apoptosis are rescued by p300. Thus, our data suggest that the ability of p300 to interact with p53 influences the physiological consequence of p53 activation. From previous studies it is known that cells expressing aberrant levels of E2F-1 can undergo p53-dependent apoptosis. In addition, we find that E2F-1 can cause apoptosis in p53-/- tumour cells and further p300, which also functions as a co-activator for the E2F/DP heterodimer, enhances the apoptotic activity of E2F-1. In conditions where E2F-1 and p53 co-operate in apoptosis E2F-1 can effectively compete for p300, causing a reduction in p53-dependent transcription. Thus, a functional interaction between p300 and either p53 or E2F-1 has a profound impact on early cell cycle progression, specifically in regulating the contrasting outcomes of cell cycle arrest and apoptosis. These results suggest a critical role for p300 in integrating and co-ordinating the functional interplay between the pathways of growth control mediated by E2F and p53.
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PMID:Functional interplay between p53 and E2F through co-activator p300. 965 36

The E2F transcription factors are key targets for the retinoblastoma protein, pRB. By inactivation of E2Fs, pRB prevents progression to the S phase. To test proliferative functions of E2F, we generated transgenic mice expressing human E2F-1 and/or human DP-1. When the hydroxymethyl glutaryl coenzyme A reductase promoter was used to express DP-1, overexpression occurred in a variety of tissues and did not confer phenotypic changes. In contrast, expression of E2F-1 from the same promoter was obtained only in testicles, in which E2F-1 overexpression caused atrophy and sterility through a process involving increased apoptosis in the germinal epithelium. This effect was potentiated by simultaneous overexpression of DP-1. Testicular atrophy as a result of overexpression of E2F-1 and DP-1 is independent of functional p53, since p53-nullizygous transgenic mice overexpressing E2F-1 and DP-1 also suffered testicular atrophy.
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PMID:E2F-1-induced p53-independent apoptosis in transgenic mice. 967 98

Approximately 30% of multiple myelomas (MMs) express cyclin D1 when assessed using immunohistochemical techniques. Cyclin D1 expression correlates with greater tumor burden in MM, because cyclin D1-positive cases are more frequently associated with extensive bone marrow involvement, i.e., high pathologic stage, than are cyclin D1-negative cases. The mechanisms that explain this association are unknown. To explore other differences between cyclin D1-positive and cyclin D1-negative MMs, we assessed 59 MMs immunohistochemically for several G1 cell-cycle regulatory proteins, including cyclin D1, E2F-1, p53, mdm-2, and p21waf-1, using routinely fixed and processed, paraffin-embedded bone marrow specimens. Twenty MMs (34%) were cyclin D1 positive, and 39 (66%) were cyclin D1 negative. Eighteen (90%) of 20 cyclin D1-positive MMs were Stage III, in contrast to 19 (49%) of 39 cyclin D1-negative MMs (P = .003). Cyclin D1-positive MMs were more likely to express E2F-1 (16/20 vs. 4/39, P < .001), p53 (11/20 vs. 10/39, P = .041), and p21waf-1 (12/20 vs. 7/39, P = .003). There was no significant difference in mdm-2 expression between these groups. We also assessed proliferation rate using an antibody specific for the Ki-67 antigen. A relatively high percentage (> 20%) of Ki-67-positive cells was found in cyclin D1-positive MMs compared with cyclin D1-negative MMs (13/20 vs. 3/39, P < 0.001). These results suggest that cyclin D1-positive MMs are more likely to possess additional derangements involving other G1 cell-cycle regulatory proteins. We speculate that these abnormalities might result in increased proliferation, thereby explaining the correlation between cyclin D1 expression and greater tumor burden.
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PMID:Expression of the cell-cycle-related proteins E2F-1, p53, mdm-2, p21waf-1, and Ki-67 in multiple myeloma: correlation with cyclin-D1 immunoreactivity. 968 85

Ultraviolet light (UV) induced DNA lesions efficiently block transcript elongation and induce the p53 response. Although p53 contributes to transcriptional activation of the p21waf1 and bax genes, accumulation of these proteins requires that these genes are free of UV induced pyrimidine dimers. We assessed the level of expression of p53 and the p53 regulated p21waf1 and bax gene products in normal diploid fibroblasts (NDF) and several nucleotide excision repair deficient fibroblasts following UV-irradiation. At low UV fluences, increased expression of p53, p21waf1 and bax was only observed in fibroblasts deficient in transcription coupled repair (TCR). Whereas p53 protein levels increased in all cell types at high UV fluences, p21waf1 levels initially decreased and then recovered in a manner dependent on TCR. At later times, expression of p21waf1 and bax was only elevated in TCR-proficient cells. The lack of TCR strongly correlated with an enhanced induction of apoptosis. Furthermore, we assessed the effect of modulation of the p53/p21waf1/pRb pathway on clonogenic survival following UV irradiation. Expression of E2F-1, E2F-4, and the large tumour antigens of SV40 and Polyomavirus conferred UV sensitivity to NDF whereas p21waf1 protected cells against UV treatment. We propose that the fluence dependent attenuation of protective functions of p53 by blockage of transcription favours apoptosis following UV exposure.
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PMID:Persistent DNA damage induced by ultraviolet light inhibits p21waf1 and bax expression: implications for DNA repair, UV sensitivity and the induction of apoptosis. 970 20


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