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

To better understand how the E2F1 transcription factor contributes to the process of cell proliferation, NIH-3T3 cell lines were generated that constitutively express either the wild-type E2F1 protein or an amino terminal deletion mutant, termed E2F1d87. Proliferating E2F1d87-expressing cells exhibit a significant lengthening of S phase relative to control and E2F1 cell lines and are hypersensitive to the cytotoxic effects of the S phase-specific antitumor drug camptothecin. This sensitivity is associated with an increase in drug-induced p53 and WAF1 levels. The E2F1 and E2F1d87 cell lines are both able to initiate, but not complete, S phase under conditions of serum starvation. However, quantitation of DNA synthesis, during culture in serum-deprived media, indicates that the E2F1d87 cell line synthesizes more DNA/cell as compared to the E2F1 cell line. Consistent with this relative increase in DNA synthesis, the E2F1d87 cell line undergoes camptothecin-induced apoptosis when cultured under conditions of serum starvation, while the control and E2F1 cell lines are unaffected by drug treatment under the same conditions. Thus, the sensitivity of the E2F1d87 cell line to camptothecin is not dependent on cell proliferation. The data presented here suggest that cell cycle parameters can be manipulated in order to enhance sensitivity of a cell to the toxic effects of specific chemotherapeutic agents.
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PMID:Expression of a deletion mutant of the E2F1 transcription factor in fibroblasts lengthens S phase and increases sensitivity to S phase-specific toxins. 754 Sep 51

Mechanisms of aging involve genetic programs and error accumulation. Cellular aging is an aspect of organismal aging from a point of view of age-dependent declines of tissue cells during the postreproductive aging process and a parallelism between enhanced individual and cellular aging in some genetic progeroid syndromes. Cellular senescence involves the gene-directed inhibition of replicative potential of cells. Cell fusion analysis has indicated that senescent normal and presenescent Werner syndrome cells cause the dominant suppression of DNA synthesis in the partner of either actively growing cells or any cells of the four complementation groups of immortalized human cells. Membrane proteins produced in senescent cells showed the biphasic DNA synthesis-inhibiting activity when assayed for young cells. Senescent cells showed the strong transcriptional repressions of early serum responsive genes (c-fos, c-jun, c-myc), late responsive genes of transcription factor E2F1 and cyclin E. In addition, the protein levels of CDK2 and cyclin E are also extremely low, with an increased level of the p53-dependent p21 Cip 1 protein which inhibits the kinase activity of cyclins/CDKs by forming complexes. Such characteristic molecular factors and mechanisms feature irreversible G1-arrest in cellular senescence.
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PMID:[Aging and cellular senescence]. 761 77

The MDM2 proto-oncogene is found amplified in a variety of tumours. The oncogenic capacity of the MDM2 protein is attributed to its ability to bind the p53 tumour-suppressor protein and mask its transcriptional activation potential. Here we show that MDM2 makes a functional contact with two cooperating transcription factors, E2F1 and DP1 (refs 4,5), which are involved in S-phase progression. MDM2 contacts the activation domain of E2F1 using residues conserved in the activation domain of p53. However, in contrast to its repression of p53 activity, MDM2 stimulates the activation capacity of E2F1/DP1. These results indicate that MDM2 not only releases a proliferative block by silencing the tumour suppressor p53, it also positively augments proliferation by stimulating the S-phase inducing transcription factors E2F1/DP1.
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PMID:Stimulation of E2F1/DP1 transcriptional activity by MDM2 oncoprotein. 779 3

Various experiments have demonstrated a role for the E2F transcription factor in the regulation of cell growth during the G0/G1/S phase transition. Indeed, overexpression of the E2F1 product, a component of the cellular E2F activity, induces DNA synthesis in quiescent fibroblasts. To provide an approach to a more detailed biochemical analysis of these events, we have made use of a recombinant adenovirus containing the E2F1 cDNA in order to efficiently express the E2F1 product in an entire population of cells. We demonstrate an induction of DNA synthesis when quiescent cells are infected with the E2F1 recombinant virus. However, we also find that the induction does not lead to a complete replication of the cellular genome, as revealed by flow cytometry. The incomplete nature of cellular DNA replication is due, at least in part, to the fact that E2F1 overexpression leads to massive cell death that is characteristic of apoptosis. This E2F1-mediated induction of apoptosis is largely dependent on endogenous wild-type p53 activity and can be subverted by introducing mutant forms of p53 into these cells or by overexpressing E2F1 in fibroblasts derived from p53-null mouse embryos. We conclude that E2F1 can induce events leading to S phase but that the process is not normal and appears to result from the activation of a cell death pathway.
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PMID:E2F1 overexpression in quiescent fibroblasts leads to induction of cellular DNA synthesis and apoptosis. 788 98

One way in which wild-type p53 is able to regulate cell cycle progression is thought to be via the induction of its downstream target gene Waf1/CIP1, thus indirectly regulating the transcriptional activity of E2F. The E2F transcription factors are known to be key effectors of the cell cycle. We report here that there is a physical and functional interaction between p53 and two of the components of the E2F transcription factors, E2F1 and DP1. The expression of wild-type p53 can inhibit the transcriptional activity of E2F, and the expression of both E2F1 and DP1 can also downregulate p53-dependent transcription. The transcriptional activity of p53 is known to be inhibited by the direct binding of mdm2, but we demonstrate here that both E2F1 and DP1 can inhibit p53 transcriptional activity independently of mdm2. Detailed studies of protein-protein interactions have provided evidence that E2F1 and its co-operating factor DP1 can complex with p53 both in vitro and in vivo.
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PMID:Physical and functional interactions between p53 and cell cycle co-operating transcription factors, E2F1 and DP1. 855 38

The product of the retinoblastoma tumor-suppressor gene (RB) is a ubiquitously expressed, 105-kDa nuclear phosphoprotein (pRB). The pRB protein negatively regulates the cellular G1/S phase transition, and it is at this point in the cell cycle that it is thought to play its role as a tumor suppressor. The growth-inhibitory effects of pRB are exerted, at least in part, through the E2F family of transcription factors. This chapter reviews the insights into the mechanism of action of the E2F family members that have been obtained through overexpression studies. Studies in RB-/- SAOS-2 cells have provided evidence in support of the hypothesis that the E2F family members are negatively regulated by pRB and the related protein p130. In particular, the results obtained are consistent with the earlier biochemical data which suggested that E2F1 is regulated primarily by pRB, and E2F4 by p130. Results relating to p107 are also discussed. Consistent with the proposed role of pRB and E2F1 as coregulators of entry into S phase, experiments have demonstrated that overexpression of E2F1 is sufficient to override the cell cycle arrests caused by serum deprivation of fibroblasts or transforming growth factor-beta (TGF-beta) treatment of mink lung epithelial cells. However, at least in the case of the serum deprivation induced arrest, the ultimate result of E2F1 overexpression is death by p53-dependent apoptosis. In light of this and other data, a model is discussed as to how functional inactivation of pRB and p53 might cooperate to promote tumorigenesis. A number of studies have demonstrated the oncogenic potential of E2F family members, at least under certain conditions. This is, again, in keeping with the notion that these proteins play a critical role in controlling proliferation.
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PMID:The cellular effects of E2F overexpression. 857 14

We have studied the abilities of different transactivation domains to stimulate the initiation and elongation (postinitiation) steps of RNA polymerase II transcription in vivo. Nuclear run-on and RNase protection analyses revealed three classes of activation domains: Sp1 and CTF stimulated initiation (type I); human immunodeficiency virus type 1 Tat fused to a DNA binding domain stimulated predominantly elongation (type IIA); and VP16, p53, and E2F1 stimulated both initiation and elongation (type IIB). A quadruple point mutation of VP16 converted it from a type IIB to a type I activator. Type I and type IIA activators synergized with one another but not with type IIB activators. This observation implies that synergy can result from the concerted action of factors stimulating two different steps in transcription: initiation and elongation. The functional differences between activators may be explained by the different contacts they make with general transcription factors. In support of this idea, we found a correlation between the abilities of activators, including Tat, to stimulate elongation and their abilities to bind TFIIH.
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PMID:Three functional classes of transcriptional activation domain. 862 70

We previously showed that expression of the bovine papillomavirus (BPV) E2 gene results in a dramatic inhibition of the proliferation of several human cervical carcinoma cell lines, including HeLa cells which contain human papillomavirus (HPV) type 18 DNA. We have assessed the status of endogenous G1 cell cycle regulatory proteins, including the tumor suppressor proteins, p53 and p105Rb, in order to investigate growth regulatory pathways in HeLa cells following E2 expression. The p53 tumor suppressor protein is stabilized following the introduction of the E2 gene into HeLa cells. This results in the induction of the p53-responsive gene encoding the cyclin dependent kinase (cdk) inhibitor, p21/WAF1, complex formation between p21/WAF1 and cdk2 and reduction of in vitro cdk2/cyclin E kinase activity. The reduced cdk kinase activity is accompanied by the accumulation of the growth inhibitory hypophosphorylated form of the tumor suppressor protein, p105Rb. The level of the p105Rb-regulated transcription factor, E2F1, is reduced, as is transcription of a variety of E2F1-regulated genes, including B-myb. Thus, the p53 growth inhibitory pathway has evidently not accumulated mutations in HeLa cells but rather appears intact. However, this pathway remains dormant, until it is mobilized by appropriate manipulations, such as the expression of the BPV E2 protein.
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PMID:Activation of the endogenous p53 growth inhibitory pathway in HeLa cervical carcinoma cells by expression of the bovine papillomavirus E2 gene. 863 1

We examined the relationship between expression of the p21 (WAF1/CIP1) inhibitor of cyclin-dependent kinases, cessation of proliferation, and terminal differentiation in the epithelia of the gastrointestinal tract. Using in situ hybridization, we performed a detailed study of patterns of p21 mRNA expression in different regions of the stomach, along the length of the intestine, and in tongue, cervix, and hair follicle. We detected strong hybridization only in cells that had ceased proliferation and begun the process of terminal differentiation. Induction of p21 transcription may serve as a useful marker for dissection of differentiation programs in these diverse epithelia. To determine the relative levels of p21 expressed in various regions of the gastrointestinal tract from the esophagus to the colon, we used quantitative RT-PCR with endogenous and exogenous sequences as internal standards. The highest levels of p21 expression were detected in the distal small intestine. To further investigate the role that cell cycle regulation may play during differentiation of intestinal epithelial cells, we examined the expression of p53, p21, cyclin D1, cyclin E, and E2F1 in the Caco-2 colon carcinoma cell line, which differentiates spontaneously after reaching confluence. p21 and p53 mRNA and protein levels increase as Caco-2 cells differentiate. In both undifferentiated and differentiated Caco-2 cells, p53 protein was not inducible by DNA damaging agents, suggesting the absence of functionally wildtype protein. Caco-2 cells should provide a useful model system for studying regulation of p21 and determining if it plays a role during intestinal epithelial cell differentiation.
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PMID:p21 (WAF1/CIP1) expression is induced in newly nondividing cells in diverse epithelia and during differentiation of the Caco-2 intestinal cell line. 883 53

p202, an interferon-inducible murine protein, is a member of the "200 family" of proteins and is primarily nuclear. p202 is a modulator of transcription; it binds several transcription factors, including NF-kappaB p50 and p65, AP-1 c-Fos and c-Jun, and E2F1, and inhibits their transcriptional activity. p202 also binds pRb, the retinoblastoma protein, and if overexpressed it retards cell proliferation. Here we report that using the yeast two-hybrid assay we found that p202 bound the murine homolog of the human p53-binding protein 1 (53BP1), a protein shown to interact with the DNA binding domain of the p53 tumor suppressor protein. p202 bound a 98amino acid segment from 53BP1. This binding was inhibited by the replacement in p202 of a histidine (from the M(F/L)HATVA(T/S) sequence that is conserved among all of the 200 family proteins) by phenylalanine. We also report that overexpression of p202 inhibited the p53-dependent expression of reporter genes containing p53-activable segments from the mdm2 and p21 genes, whereas a decrease in the p202 level (in consequence of the expression of 202 antisense RNA) resulted in an increase in the p53-dependent expression of these reporters. Expression of the 53BP1 segment binding to p202 overcame the inhibition by overexpressed p202 of the transcription of reporters mediated by the p53 or the AP-1 transcription factors and of the proliferation of yeast.
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PMID:p202, an interferon-inducible modulator of transcription, inhibits transcriptional activation by the p53 tumor suppressor protein, and a segment from the p53-binding protein 1 that binds to p202 overcomes this inhibition. 891 Mar 40


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