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

Activation of the p53 protein can lead to apoptosis and cell cycle arrest. In contrast, activation of the signalling pathway controlled by the Kit receptor tyrosine kinase prevents apoptosis and promotes cell division of a number of different cell types in vivo. We have investigated the consequences of activating the Kit signalling pathway by its ligand Steel factor on these opposing functions of the p53 protein in Friend erythroleukemia cells. A temperature-sensitive p53 allele (Val-135) was introduced into the Friend erythroleukemia cell line (DP-16) which lacks endogenous p53 expression. At 38.5 degrees C, the Val-135 protein maintains a mutant conformation and has no effect on cell growth. At 32 degrees C, the mutant protein assumes wild-type properties and induces these cells to arrest in G1, terminally differentiate, and die by apoptosis. We demonstrate that Steel factor inhibits p53-mediated apoptosis and differentiation but has no effect on p53-mediated G1/S cell cycle arrest. These results demonstrate that Steel factor functions as a cell survival factor in part through the suppression of differentiation and apoptosis induced by p53 and suggest that cell cycle arrest and apoptosis may be separable functions of p53.
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PMID:Regulation of p53-mediated apoptosis and cell cycle arrest by Steel factor. 852 62

The cyclin-dependent kinase inhibitor p21WAF1/Cip1 (p21) inhibits cellular proliferation and has been implicated in p53-dependent apoptosis. In this study, we examined the regulation of p21 in the K562 erythroleukemia cell line using a human temperature-sensitive mutant of p53, 143Ala. We showed that 143Ala at the permissive temperature (32 degrees C) activated the expression of p21. Stable cell lines expressing 143Ala or other p53 mutants were established. We then examined whether elevation of p21 promotes apoptosis and sensitized cells to radiation-induced apoptosis. Our results showed that p21 elevation did not promote or sensitize K562 cells to apoptosis.
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PMID:Activation of p21WAF1/Cip1 expression by a temperature-sensitive mutant of human p53 does not lead to apoptosis. 857 Jan 82

Retroviral insertional activation of Fli-1 is the first detectable genetic alteration associated with F-MuLV-induced primary erythroleukemias, while mutations within p53 are only observed in Epo-dependent (ED) cell lines derived from syngeneic mice serially transplanted with F-MuLV-induced primary erythroleukemias. In this study we have determined the mechanism of growth factor independence in several Epo-independent (EI) cell lines established from adult mice previously injected with ED-erythroleukemia cell lines or serially transplanted primary tumor cells. Here we have shown constitutive expression of the Epo gene in 12 of 15 (80%) EI-erythroleukemia cell lines. Among these 12 cell lines, eight were shown to possess clonal rearrangement of the Epo gene which could be detected in the tumors used to establish the majority of these EI-cell lines. Analysis of the pattern of proviral integration revealed that the activation of the Epo gene in these cell lines is independent of retroviral insertional mutagenesis, but apparently the result of genomic rearrangements. Furthermore, the acquisition of growth factor independence by these leukemic cells confers a selective growth advantage in vivo and is associated with enhanced tumorigenicity. Together these observations suggest that the activation of the Epo gene in the large majority of these F-MuLV-induced erythroleukemic cell lines establishes an autocrine loop resulting in the constitutive activation of the Epo receptor signal transduction pathway, thereby conferring a growth and survival advantage in vito and in vitro.
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PMID:Activation of the erythropoietin gene in the majority of F-MuLV-induced erythroleukemias results in growth factor independence and enhanced tumorigenicity. 862 56

Mice infected with Friend Leukemia Virus (FLV) rapidly develop erythroleukemia and severe immune deficiency which resembles human AIDS. We have reported that mice infected with a lethal dose of FLV can be 100% cured by 150 cGy total body irradiation (TBI). This curative effect was associated with restoration of cellular immunity which was compromised by the virus. This restoration may result from activation of the IFN-gamma system and IL-2 production. Our research work further demonstrated that no spleen focus-forming virus (SFFV) specific mRNAs, no 6.0kb SFFV fragments and SFFV envelope glycoproteins were detectable in FLV-infected mice treated with low dose TBI. Predicated on our report, del Regato has initiated clinical trials to treat AIDS patients with low dose TBI. The preliminary results are encouraging and the study is continuing. We have also studied the effects of low dose TBI on the expression of the P53 gene. The results show loss or inactivation of P53 tumor suppressor genes in FLV-infected mice, but P53 expression was restored in FLV-infected mice treated by low dose TBI. It is intriguing to speculate that in the curative effect of low dose TBI on mice infected with retrovirus, the P53 tumor suppressor gene may play an important role. It would be of interest to see if this type of treatment, which was well tolerated by mice, would be beneficial in other types of virally induced disease, including AIDS.
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PMID:Curative effect of split low dosage total-body irradiation on murine AIDS induced by Friend virus: the results and the possible mechanism. 874

Retroviral insertional activation of the Fli-1 proto-oncogene is the first genetic event associated with the induction of erythroleukemias by the Friend murine leukemia virus (F-MuLV). Mutations within p53, which are only detected in cell lines established from transplanted tumors, have been previously shown to be associated with the immortalization of erythroleukemic cells in culture. In this study, we have demonstrated that primary erythroleukemic cells grown in liquid culture undergo rapid apoptosis independent of the stabilization of wild-type p53 protein. Further confirmation that the programmed cell death observed for liquid-cultured F-MuLV-induced primary erythroleukemic cells is largely p53 independent was provided by experimentation with a transgenic mouse line containing multiple copies of the dominant negative mutant p53Pro-193 allele. Erythroleukemic cells taken from tumor-bearing transgenic mice expressing high levels of the mutant p53Pro-193 undergo programmed cell death in culture in a manner that is largely identical to that observed for tumor cells derived from nontransgenic littermates. Furthermore, the rate of development of F-MuLV-induced erythroleukemias for both p53Pro-193-transgenic and nontransgenic littermates are similar. Moreover, cytogenetic analysis indicates that primary erythroleukemia cells are diploid, whereas chromosomal aberrations were observed in all established cell lines. These results are consistent with the notion that mutations within the p53 tumor suppressor gene affect genomic stability, subsequently leading to changes in gene expression that are associated with the immortalization of erythroid progenitor cells.
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PMID:p53-independent tumor growth and in vitro cell survival for F-MuLV-induced erythroleukemias. 895 33

Camptothecin, an antitumor drug that specifically targets topoisomerase I, induced IW32 erythroleukemia cells to differentiate along the erythroid pathway, as demonstrated by the increased mRNA and protein expression of hemoglobin. Unlike other chemically induced erythroleukemia cell differentiation, no c-myc mRNA down-regulation was observed in the early phases of drug treatment. Among the heme-synthesizing enzyme mRNAs that were analyzed, only that of the erythroid-specific delta-aminolevulinic acid synthase (ALAS-E) was stimulated. Vanadate or benzylphosphonic acid, which inhibited protein tyrosine phosphatases (PTPase), blocked the camptothecin-induced differentiation. Maximal inhibition was attained if vanadate was added within the first 6 hr of camptothecin treatment, after which vanadate gradually lost its effectiveness. Camptothecin-induced expression of beta-globin or ALAS-E transcript levels was inhibited in the presence of cycloheximide or vanadate. It was also shown that vanadate blocked differentiation of IW32 cells induced by sodium butyrate, VM-26, and p53. Increased PTPase activity could be observed 48 hr after cells were treated with camptothecin, VM-26, or sodium butyrate. Analysis of PTPase activity in the course of camptothecin treatment showed elevated levels of PTPase in the cytosol and the nucleus, with a greater increase demonstrated in the cytosol than in the nucleus. Our results suggest that by stimulating the beta-globin and ALAS-E gene expression, PTPase plays a critical role in the induced differentiation of IW32 erythroleukemia cells.
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PMID:Protein tyrosine phosphatase-dependent activation of beta-globin and delta-aminolevulinic acid synthase genes in the camptothecin-induced IW32 erythroleukemia cell differentiation. 910 19

Friend leukemia virus complex (FLV) consists of replication-defective, Friend spleen focus-forming virus (F-SFFV) and replication-competent, Friend murine leukemia virus (F-MuLV). We produced transgenic mice possessing F-SFFV gp55 gene and clarified that the gp55 glycoprotein encoded by F-SFFV env-related gene is, by itself, responsible for the initiation of erythroleukemia. The occurrence of erythroleukemia, however, is sporadic in these mice. Erythroleukemia cell lines established from these mice possessed mutations in the p53 allele. One had a temperature-sensitive mutant p53 allele, p53Val-135 and showed induction of apoptosis by expressing a wild-type p53 protein at 32 degrees C. Superinfection of the mice with Moloney murine leukemia virus (Mo-MuLV) conferred 100% induction of erythroleukemia, mutating p53 gene or activating Spfi-1 gene by insertional events. Activation of the JAK/STAT pathway, which is involved in cytokine signaling, was investigated in the gp55 signaling mediated by the erythropoietin receptor. JAK1 and STAT5 were constitutively tyrosine-phosphorylated but the DNA binding activity of STAT5 was not induced.
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PMID:Pathogenesis of Friend leukemia virus. 920 27

We have generated a series of murine erythroleukemia clones that ectopically express a temperature sensitive mutant p53 allele. In many clones, activation of p53 at low temperature resulted in the accumulation of cells in G1 and in apoptosis. Several cytokines including erythropoietin, IL-3 and the ligand for the Kit receptor blocked p53-dependent apoptosis in p53ts-expressing cells at 32 degrees C. Cytokine-treated cells were reversibly arrested in G1 and resumed growth upon return to 37 degrees C. Certain clones exhibited only a G1 arrest in response to p53 activation at 32 degrees C. One of the these clones secreted erythropoietin and another secreted IL-3. We tested the possibility that autocrine secretion of IL-3 played a role in preventing apoptosis and showed that disruption of the autocrine loop by cell dilution or with neutralizing antibodies to IL-3 restored p53-dependent apoptosis at 32 degrees C. Thus, two properties of p53 protein, namely, its ability to arrest cells in G1 and its ability to promote apoptosis could be uncoupled by cytokines acting as survival factors.
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PMID:p53-mediated cell cycle arrest and apoptosis. 920 79

Spi-1/PU.1 is a myeloid- and B-cell specific transcription factor which is also involved in Friend virus-induced murine erythroleukemia. The pre-leukemic phase of Friend erythroleukemia results from activation of the erythropoietin receptor (EpoR) by the spleen focus forming virus (SFFV) envelope glycoprotein, followed by the emergence of leukemic clones characterized by overexpression of Spi-1 and mutation of the p53 tumor suppressor gene. We developed a heterologous system to analyze the contribution of these alterations to the induction of primary erythroblast transformation. Avian erythroblasts expressing the activated mouse EpoR(R129C) differentiated into erythrocytes in response to hEpo. Expression of Spi-1 in these cells inhibited this ability to differentiate and rescued the cells from the apoptotic cell death program normally induced upon hEpo withdrawal. Although devoid of any effect by itself, a mutant p53 cooperated with Spi-1 and EpoR(R129C) to reinforce both phenotypes. Analysis of erythroblasts co-expressing Spi-1 and the wild-type mouse EpoR showed that differentiation arrest and inhibition of apoptosis depended on specific cooperation between Spi-1 and EpoR(R129C). This cooperation was also required to induce the sustained proliferation of differentiation-blocked erythroblasts in response to ligand activation of the endogenous tyrosine kinase receptor c-Kit. These results show that Spi-1/PU.1 requires signals emanating from specific cytokine and growth factor receptors to affect the survival, proliferation and differentiation control of primary erythroblasts. They also suggest that the function of Spi-1/PU.1 in the late phase of Friend leukemia requires specific signaling from the gp55-modified EpoR generated during the early phase of the disease.
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PMID:Cooperation of Spi-1/PU.1 with an activated erythropoietin receptor inhibits apoptosis and Epo-dependent differentiation in primary erythroblasts and induces their Kit ligand-dependent proliferation. 931 23

Development of colon cancer is a multistep process frequently involving mutations in both the APC and p53 tumor suppressor genes. In this study we treated the HCT-116 colon cancer cell line with alkylating agents including N-methyl-N'-nitro-N-nitrosoguanidine (MNNG),which is known to cause colon cancer in animals, and examined the expression of both APC and p53 genes. Exposure of cells with MNNG caused an 8-12-fold increase in the level of APC mRNA and protein. APC induction was shown to result from increased nuclear transcription of the APC gene and correlated with a concomitant increase in the p53 protein level after MNNG treatment. A necessary role for p53 in APC gene regulation is supported by the failure of MNNG to induce APC expression in cell lines either expressing very low levels of p53 (HeLa cells) or no p53 (K562 erythroleukemia cells). The overexpression of wild-type p53 gene into HCT-116 cells mimicked the effect of MNNG-induced expression of APC mRNA. A direct causal role for p53 in APC gene regulation was further evaluated by transfecting the wild-type p53 gene into K562 cells and observing a 5-fold increase in the APC gene expression. These results support a model featuring a direct link between p53 and APC in response to alkylation-induced DNA damage and suggest a novel role for p53 in a stress-response pathway involving APC.
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PMID:Activation of adenomatous polyposis coli (APC) gene expression by the DNA-alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine requires p53. 938 95


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