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)

Burkitt-type acute leukemia cells were present in the bone marrow of a patient with B-prolymphocytic leukemia diagnosed from peripheral blood cell morphology. Immunophenotype analysis confirmed morphological patterns. Cytogenetic and fluorescence in situ hybridization (FISH) analysis showed an identical t(8;22)(q24;q21) with MYC locus rearrangement in blood and bone marrow cells, with additional chromosome abnormalities in the bone marrow. In addition, the loss of one copy of the TP53 gene and identical IGH DNA clonal rearrangements were shown with FISH and polymerase chain reaction analysis respectively in the two types of leukemic cells. These data indicated the common origin of the two coexisting leukemias and are the first example of such occurrence in a leukemic patient.
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PMID:Burkitt-type acute leukemia in a patient with B-prolymphocytic leukemia: evidence for a common origin. 1586 Mar 62

Apaf-1 is important for tumor suppression and drug resistance because it plays a central role in DNA damage-induced apoptosis. Inactivation of the Apaf-1 gene is implicated in disease progression and chemoresistance of some malignancies. In this study, we attempted to clarify the role of Apaf-1 in leukemogenesis. Apaf-1 mRNA levels were below the detection limit or very low in 5 of 20 human leukemia cell lines (25%) and 5 of 12 primary acute myeloblastic leukemia cells (42%). There were no gross structural abnormalities in the Apaf-1 gene in these samples. Expression of factors regulating Apaf-1 transcription, such as E2F-1, p53, and Sp-1, did not differ between Apaf-1-positive and Apaf-1-negative cells. Methylation of CpG in the region between +87 and +128 of the Apaf-1 gene was almost exclusively observed in Apaf-1-defective cell lines. Treatment of these cells with 5-aza-2'-deoxycytidine, a specific inhibitor of DNA methylation, restored the expression of Apaf-1. Furthermore, we showed that the region between +87 and +128 could act as a repressor element by recruiting corepressors such as methylated DNA-binding domain 2 and histone deacetylase 1 upon methylation. Overexpression of Dnmt1, a mammalian maintenance DNA methyltransferase, was associated with Apaf-1 gene methylation. DNAs from Dnmt1-overexpressing cells were more resistant to digestion with methylation-sensitive enzyme HpaII than those from cells with low Dnmt1 expression, suggesting that Dnmt1 mediates aberrant methylation of multiple genes. In conclusion, methylation silencing is a mechanism of the inactivation of Apaf-1 in acute leukemia, and Dnmt1 overexpression may underlie hypermethylation of the Apaf-1 gene.
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PMID:Methylation silencing of the Apaf-1 gene in acute leukemia. 1597 51

In multiple types of acute leukemia,a portion of the MLL protein is fused to a variety of other unrelated proteins. The activity of leukemic MLL fusions is believed to be directly contributing to the conversion of normal bone marrow cells into leukemic cancer cells. However, the mechanism of this process has not been fully elucidated. We have recently found that the MLL leukemic fusions can abolish the activity of P53 tumor suppressor protein that actively guards against the appearance of cancer by instructing damaged cells to self-destruct. In contrast to the vast majority of cancers where p53 gene is mutated, very few p53 mutations have been found in leukemias. Our findings suggest that leukemic fusions contribute to disease progression, at least in part, by suppressing the function of P53, which,if proven,may present a novel opportunity to re-activating the P53 pathway in leukemic cells thereby identifying a rational therapeutic approach for managing leukemias where MLL fusions are detected.
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PMID:Functional inactivation of P53 as a potential mechanism of MLL leukemogenesis. 1706 17

Apoptosis resistance is crucially involved in cancer development and progression, represents the leading cause for failure of anticancer therapy and is caused, for example, by downregulation of proapoptotic intracellular signaling molecules such as caspase-8. We found that the cytotoxic drugs methotrexate (MTX) and 5-fluorouracil (5-FU) were both able to sensitize resistant tumor cells for induction of apoptosis by p53-mediated upregulation of caspase-8. Increase in caspase-8 messenger RNA and protein expression disabled tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced proliferation and restored sensitivity toward TRAIL-induced apoptosis which was inhibited by transfection of p53 decoy oligonucleotides, p53 shRNA and caspase-8 shRNA. Upregulation of caspase-8 and sensitization toward TRAIL-induced apoptosis was found both in a broad panel of tumor cell lines with downregulated caspase-8 and in TRAIL-resistant primary tumor cells of children with acute leukemia. Taken together, we have identified caspase-8 as an important p53 target gene regulated by cytotoxic drugs. These findings highlight a new drug-induced modulation of physiological apoptosis pathways, which may be involved in successful anticancer therapy using MTX and 5-FU in leukemia and solid tumors over decades.
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PMID:Cytotoxic drug-induced, p53-mediated upregulation of caspase-8 in tumor cells. 1763 40

Leukemia stem cells (LSCs) are thought to play a central role in the pathogenesis of acute leukemia and likely contribute to both disease initiation and relapse. Therefore, identification of agents that target LSCs is an important consideration for the development of new therapies. To this end, we have previously demonstrated that the naturally occurring compound parthenolide (PTL) can induce death of human LSCs in vitro while sparing normal hematopoietic cells. However, PTL has relatively poor pharmacologic properties that limit its potential clinical use. Consequently, we generated a family of PTL analogs designed to improve solubility and bioavailability. These studies identified an analog, dimethylamino-parthenolide (DMAPT), which induces rapid death of primary human LSCs from both myeloid and lymphoid leukemias, and is also highly cytotoxic to bulk leukemic cell populations. Molecular studies indicate the prevalent activities of DMAPT include induction of oxidative stress responses, inhibition of NF-kappaB, and activation of p53. The compound has approximately 70% oral bioavailability, and pharmacologic studies using both mouse xenograft models and spontaneous acute canine leukemias demonstrate in vivo bioactivity as determined by functional assays and multiple biomarkers. Therefore, based on the collective preclinical data, we propose that the novel compound DMAPT has the potential to target human LSCs in vivo.
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PMID:An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. 1780 95

Cytosine arabinoside (1-beta-D-arabinofuranosylcytosine; Ara-C) is the most important antimetabolite used to induce remission in acute leukemia, but cellular resistance to Ara-C reflects a poor prognosis in cancer chemotherapy. To further investigate the mechanisms of resistance to Ara-C, we have established Ara-C-resistant NALM-6 cells. The activation of nuclear factor kappaB (NF-kappaB) was accompanied by the acquisition of Ara-C resistance. Telomerase activity has also increased with the acquisition of Ara-C resistance. The expression of Bid, Bax, or p53 proteins have been shown to increase correlated with the acquisition of Ara-C resistance. In contrast to the increase in these proteins, Bcl-2, Bcl-x, and Bag-1 proteins remained unchanged with the acquisition of Ara-C resistance. Fas expression increased with the acquisition of Ara-C resistance in the late stage. The induction of apoptosis and reduction of cell viability by cytotoxic anti-Fas antibody was more susceptible in resistant cells than parental cells. In conclusion, this report has shown that resistance to Ara-C up-regulates the activation of NF-kappaB, telomerase activity and Fas expression.
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PMID:Resistance to Ara-C up-regulates the activation of NF-kappaB, telomerase activity and Fas expression in NALM-6 cells. 1797 77

P53 mutation has been reported in various solid tumors, acute leukemia and myelodysplastic syndrome (MDS), but the diagnostic significance of p53 in MDS remains to be determined. The purpose of the present paper was to examine p53 mutation and immunostaining of the same patients, because there have been few reports of simultaneous analysis of these markers. Seven p53 mutations were observed among 37 MDS and 11 cases of overt leukemia transformed from MDS (MDS-OL). Mutated p53 mainly observed in high-risk MDS had more intense p53 staining than in MDS with wild-type p53 overexpression. Aplastic anemia (AA) produced no p53 staining. The percentage of p53 staining in MDS (71%) was higher than that of mutated p53 (11%) but did not reach 100% of MDS cases studied, therefore the authors attempted to differentiate MDS, especially refractory anemia (RA) and AA, using a combination of p53 immunostaining, hemoglobin F (HbF) immunostaining and chromosome abnormality, because HbF of erythroblasts was reportedly observed in MDS RA but not in AA. Most MDS/MDS-OL (47/48) had at least one positive marker. Among 11 AA cases, only two were positive for HbF. The present results suggest that the combination of these three markers is useful to discriminate MDS from AA.
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PMID:Characterization of myelodysplastic syndrome and aplastic anemia by immunostaining of p53 and hemoglobin F and karyotype analysis: differential diagnosis between refractory anemia and aplastic anemia. 1847 14

The NUP98-HOXD13 (NHD13) fusion gene occurs in patients with myelodysplastic syndrome (MDS) and acute nonlymphocytic leukemia (ANLL). We reported that transgenic mice expressing NHD13 develop MDS, and that more than half of these mice eventually progress to acute leukemia. The latency period suggests a requirement for at least 1 complementary event before leukemic transformation. We conducted a candidate gene search for complementary events focused on genes that are frequently mutated in human myeloid leukemia. We investigated 22 ANLL samples and found a high frequency of Nras and Kras mutations, an absence of Npm1, p53, Runx1, Kit and Flt3 mutations, and a single Cbl mutation. Our findings support a working hypothesis that predicts that ANLL cases have one mutation which inhibits differentiation, and a complementary mutation which enhances proliferation or inhibit apoptosis. In addition, we provide the first evidence for spontaneous collaborating mutations in a genetically engineered mouse model of ANLL.
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PMID:Leukemic transformation in mice expressing a NUP98-HOXD13 transgene is accompanied by spontaneous mutations in Nras, Kras, and Cbl. 1856 22

We analyzed expression of p53-induced gene 7 (pig7), at the transcript level, in bone marrow samples from patients with de novo acute leukemia (AL) and normal controls by quantitative reverse transcription PCR (RT-PCR), and revealed a markedly decreased pig7 expression in the patient group, as well as in the relapsed/refractory patients compared with those at initial diagnosis. By endonuclease analysis, we detected only one form of pig7 transcript, i.e., small integral membrane protein of late endosome (simple), in AL patients. In addition, up-regulated pig7 expression could be detected in differentiated leukemic cells induced by drugs. Transient expression of pig7 in leukemic cells exhibited no evident effect on cell proliferation and differentiation, but could intensify inhibitory efficacy of etoposide (VP16) and daunorubicin (DNR). Conclusively, the present study provides the evidence that pig7 is a silenced gene affected by perturbed differentiation in acute leukemia and restoration of pig7 expression sensitizes leukemic cells to chemotherapeutic agents.
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PMID:Expression of pig7 gene in acute leukemia and its potential to modulate the chemosensitivity of leukemic cells. 1867 16

Oncoprotein inhibitory member of the ASPP family (iASPP) is a key inhibitor of tumor suppressor p53. Our previous study revealed that the expression of iASPP in acute leukemia (AL) patients was higher than that of normal control which implied that iASPP might play an important role in the pathogenesis and/or disease progression of AL. In this study, the iASPP expression was blocked by RNA interference (RNAi) in two leukemic cell lines, Nalm6 and K562, to explore the effects of iASPP on leukemia cells. The results indicated that down-regulation of endogenous iASPP increased p53-dependent apoptosis of leukemia cells. Thus, iASPP could be a molecular target in leukemia therapy.
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PMID:siRNA-mediated down-regulation of iASPP promotes apoptosis induced by etoposide and daunorubicin in leukemia cells expressing wild-type p53. 1948 1


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