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)

A novel GM-CSF-dependent myeloid cell line, OHN-GM, was established from a patient who developed acute myelogenous leukaemia (AML) as a consequence of myelodysplastic syndrome (MDS). As the patient had previously received cytotoxic chemotherapy for Hodgkin's disease, the MDS and AML were probably related to such therapy. Sequential karyotypic analysis established a del(5q) as the initial cytogenetic abnormality. Additional alterations, including t(10;13)(q24;q14), had developed subsequently during disease progression. Southern blot analysis of OHN-GM cells suggested deletion of one allele of the IRF-1 gene, although no aberrant transcripts were detected. Fluorescence in situ hybridization analysis revealed the deletion of the Rb gene due to the t(10;13)(q24;q14) translocation, and Western blot analysis demonstrated the absence of Rb protein in OHN-GM cells. Finally, the OHN-GM cells exhibited two missense point mutations in highly conserved regions of the p53 gene. These observations suggest that a multistep process, involving alterations of Rb and p53 genes, may have contributed to the patient's disease development and progression. To our knowledge, OHN-GM is the first cell line derived from a therapy-related AML. These cells may aid the investigation of leukaemogenesis as well as the biology of secondary leukaemia.
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PMID:Alterations of p53 and Rb genes in a novel human GM-CSF-dependent myeloid cell line (OHN-GM) established from therapy-related leukaemia. 926 38

The AML14.3D10 human myeloid leukemic cell line expresses receptors for granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-5 (IL-5), but not IL-3. We have found that this cell line produces GM-CSF in amounts up to 113 pg/ml in culture supernatants. Deprivation of endogenous GM-CSF by addition of neutralizing anti-GM-CSF antibody strongly inhibits proliferation of the cells, suggesting a GM-CSF autocrine growth mechanism. To examine whether endogenously produced GM-CSF activates intracellular GM-CSF/IL-3/IL-5-related signal transduction pathways, we performed antiphosphotyrosine immunoblotting of cell lysates of AML14.3D10 cells before and after deprivation of endogenous GM-CSF. We found constitutive tyrosine-phosphorylation of a number of proteins in AML14.3D10 that could not be detectably increased by the addition of exogenous GM-CSF, IL-3, or IL-5. However, GM-CSF-deprived cells demonstrated a marked increase in phosphorylation of proteins of identical molecular mass following addition of GM-CSF and IL-5, but not IL-3, consistent with the receptor expression of the cells and the known use of the same signaling pathways by the three cytokines. This suggests that AML14.3D10 cells use endogenously produced GM-CSF to activate signal transduction pathways, interfering with activation by exogenous cytokine until the endogenous stimulation is removed. We then assessed the activation of the beta-subunit common to the GM-CSF/IL-3/IL-5 receptors (beta c), JAK2 and p53/56 lyn, known to be involved in the common signaling pathways of the three cytokines. We found that phosphorylation of beta c and JAK2 in response to GM-CSF and IL-5 could be markedly enhanced by depriving cells of endogenous GM-CSF. Constitutive hyperphosphorylation of lyn was found in AML14.3D10 cells, and no further activation of lyn in response to cytokine was demonstrable in GM-CSF-deprived cells, suggesting that lyn is activated in this cell line by a mechanism other than GM-CSF. These studies represent the first demonstration of autocrine activation of intracellular cytokine signaling pathways by malignant hematopoietic cells. Because the addition of anti-GM-CSF to cell cultures improved responsiveness of intracellular signal transducing molecules to exogenous GM-CSF and IL-5, it can be inferred that endogenously produced GM-CSF exerts its effects by secretion and binding to surface GM-CSF receptors, although an intracellular component to signaling cannot be excluded. These observations provide further information regarding an autocrine contribution to leukemic cell growth, and establish a new model for study of these events.
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PMID:Autocrine activation of the IL-3/GM-CSF/IL-5 signaling pathway in leukemic cells. 932 48

Human T-cell leukemia virus type-I (HTLV-I), the etiologic agent of adult T-cell leukemia (ATL) transforms human T cells both in vivo and in vitro. However, the long latency period between infection and development of ATL, as well as the small fraction of the infected population that actually develops this disease, suggest that factors in addition to the virus are involved in its pathogenesis. Mutation of tumor suppressor gene p53 has been found in both HTLV-I-transformed T-cell lines and ATL cases at relatively low frequency. However, increasing evidence supports p53 functional impairment in HTLV-I-transformed T cells. Tax, the major transactivator of HTLV-I, is critical for the initial events involved in transformation. We have considered the possibility that p53 may regulate transcription of viral and cellular genes important for viral replication and transformation. Inactivation of p53 function might then permit constitutive expression of these viral and cellular genes. We have investigated the effects of wild-type and mutant p53 on Tax-mediated activation of the HTLV-I long terminal repeat (LTR) and the promoters of several cellular genes including the interleukin (IL)-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF ), and IL-2 receptor alpha chain gene. Jurkat, HuT78, and U937 cells were cotransfected with plasmids containing a chloramphenicol acetyltransferase (CAT ) reporter gene under viral or cellular promoter control and the Tax expression vector, in addition to vectors for a wild-type or mutant p53. Wild-type p53 is a potent repressor of viral and cellular activation by Tax. Mutations within p53 severely inhibit this downregulation. We also show that wild-type p53 suppresses transcription from the HTLV-I LTR in Jurkat-Tax, a T-cell line stably expressing Tax, and MT-2, a HTLV-I-transformed T-cell line. Wild-type, but not mutant, p53 interfered with the binding of TATA-binding protein (TBP) to the TATA motif of the HTLV-I LTR. These results suggest that p53 inactivation may lead to upregulation of viral and cellular genes and may also be important for establishment of productive viral infection and development of ATL.
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PMID:Repression of transcription from the human T-cell leukemia virus type I long terminal repeat and cellular gene promoters by wild-type p53. 938 10

Immunotherapy targeting p53 missense mutations, which occur in nearly half of all human tumors, is limited by several factors, including the constraints of antigen processing and presentation. Due to the accumulation of mutated p53 molecules in tumors expressing p53 mutations, an alternative approach would be to target wild-type sequence, CTL-defined p53 epitopes. Obviously, the possibility of an autoimmune response is a major potential drawback to this therapy. Immunization of BALB/c mice with bone marrow-derived dendritic cells (DC) generated in the presence of GM-CSF/IL-4 and prepulsed with the H-2Kd-binding wild-type p53(232-240) peptide has been shown to induce anti-peptide CTL. These effectors were cross-reactive against sarcomas expressing p53 missense mutations outside of the p53(232-240) epitope, but not within it. Mitogen-activated splenocytes, which express elevated levels of p53, were not sensitive to these CTL. The p53 peptide-pulsed DC-based vaccine was shown to be effective in inducing tumor rejection in immunization and therapy models in the absence of any observable deleterious effect on naive mice. The murine model has now been extended to include the use of genetically modified DC-based vaccines as well.
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PMID:p53-based immunotherapy of cancer. 941 45

Adenovirus infection of CD34+ hematopoietic stem/progenitor cells is dependent on the multiplicity of infection (MOI), time of incubation, the volume in which the co-incubation occurs and the presence or absence of growth factors. Studies revealed that a brief co-incubation (1-8 hours), resulted in low levels of transgene expression, suggesting that adenovirus infection of CD34+ cells occurs slowly, and optimal transduction requires a 24 hour exposure to adenovirus. Infection by Ad/beta-gal or Ad/p53 at a MOI of 500:1 provided a high transduction efficiency but inhibited hematopoietic function. However, treatment at a MOI of 50-100 resulted in efficient transduction (10.7-15.7% positive) without detectable toxicity. Secondary proof of adenovirus transgene expression was demonstrated by detection of mRNA for p53 in Ad/p53 infected stem cells. We conclude that a 24 hour exposure to recombinant adenovirus encoding p53 or beta-gal, at a MOI of 50-100 is optimal for in vitro gene transfer to BM cells and has no significant effect on hematopoietic function. Adenovirus-mediated transduction of BM cells can also be modulated by growth factors (IL-3, GM-CSF and G-CSF) with improved gene delivery and maintenance of hematopoietic function. In summary, adenovirus vectors can be used to transiently transduce stem cells, and conditions have been defined to maximize expression and limit inhibitory effects on CD34+ cells. These data support continued investigation of this vector for local cytokine delivery and purging of stem cell products.
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PMID:Enhancement of adenovirus-mediated gene transfer to human bone marrow cells. 964 58

Immunohistological methods did not elucidate the etiology and pathogenesis of Hodgkin's disease. In "classical" cases the immunophenotype is based on evidence of three markers: CD30+, CD15+, CD20-. Despite the use of more recent methodical approaches a considerable percentage of Hodgkin and RS cells with CD15 antibody is negative. The Epstein-Barr virus (EBV) plays an important part in the development of malignant disease and at the same time a number of nuclear antigens can be detected: EBNA-1, EBNA-2, EBNA-3a,-3b,-3c,LP. Also latent membrane proteins LMP-1, -2a, -2b and two small ribonucleic acids described as EBER-1, EBER-2. Bcl-2 protein was detected in the majority of malignant lymphomas which reduces its value in differential diagnostic reflections. In Hodgkin and RS cells its positivity is not due to translocation or other disorders of the cell genoma. In these cells the expression of mRNA for bcl-2 is much more constant. Most probably there is no cooperation of bcl-2 and p53. Co-expression of the two genes was found only in a small percentage of patients with m.Hodgkin. The varied morphological picture in particular in the mixed type of m. Hodgkin is most probably associated with the formation and release of cytokines, factors which stimulate cell colonies (IL-3, GM-CSF, G-CSF, M-CSF). Non-tumourous cells chemotactically attracted to sites of tumour cells release further cytokines e.g. TGF-beta, IL-1, Il-2, which participate in the overall morphological appearance of the lesion.
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PMID:[Molecular biology aspects of Hodgkin's disease]. 982 63

Cationic liposome-DNA complex (CLDC)-based intravenous gene delivery targets gene expression to vascular endothelial cells, macrophages and tumor cells. We used systemic gene delivery to identify anti-angiogenic gene products effective against metastatic spread in tumor-bearing mice. Specifically, CLDC-based intravenous delivery of the p53 and GM-CSF genes were each as effective as the potent antiangiogenic gene, angiostatin, in reducing both tumor metastasis and tumor angiogenesis. Combined delivery of these genes did not increase anti-tumor activity, further suggesting that each gene appeared to produce its antimetastatic activity through a common antiangiogenic pathway. CLDC-based intravenous delivery of the human wild type p53 gene transfected up to 80% of tumor cells metastatic to lung. Furthermore, it specifically induced the expression of the potent antiangiogenic gene, thrombospondin-1, indicating that p53 gene delivery in vivo may inhibit angiogenesis by inducing endogenous thrombospondin-1 expression. CLDC-based delivery also identified a novel anti-tumor activity for the metastasis suppressor gene CC3. Thus, CLDC-based intravenous gene delivery can produce systemic antiangiogenic gene therapy using a variety of different genes and may be used to assess potential synergy of combined anti-tumor gene delivery and to identify novel activities for existing anti-tumor genes.
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PMID:Systemic gene delivery expands the repertoire of effective antiangiogenic agents. 1022 95

Human granulocyte-macrophage colony-stimulating factor (hGM-CSF) induces proliferation and sustains viability of the mouse interleukin (IL)-3 dependent lymphoid cell line BA/F3 expressing the hGM-CSF receptor. Caspase-3 like enzyme activity and DNA fragmentation were augmented by depletion of this factor from the cell, and exposure to gamma irradiation accelerated kinetics of these events. Anti gamma irradiation-induced apoptosis occurred through various mutant GM-CSF receptors and only the box1 region was essential while the C terminal region, including tyrosine residues which are required for MAPK cascade activation, was dispensable. Consistent with this notion, the addition of PD98059 had no effect on this activity thereby indicating that activation of MAPK is not essential for the activity. As expected, gamma irradiation increased p53 protein and bax mRNA levels and the presence of hGM-CSF dramatically modulated bax/bcl-X(L) ratio. The PI-3K specific inhibitor wortmannin did not affect hGM-CSF dependent anti gamma irradiation induced apoptosis nor bcl-X(L) induction, thus bcl-X(L) but not PI-3K pathway seems to be involved in hGM-CSF dependent anti gamma irradiation-induced apoptosis. It is well documented that the boxl region is essential for GM-CSF dependent activation of JAK2 and JAK2 specific inhibitor AG490 suppressed anti gamma, irradiation-induced apoptosis by hGM-CSF. An artificial JAK2 activating molecule in which extracellular and the transmembrane of beta(c) fused with whole JAK2 can sustain BA/F3 cells survival and proliferation mIL-3 independently, but these cells are susceptible to gamma irradiation. Furthermore GyrB/Jak2, which can activate STAT5 but not the MAPK cascade nor survival of BA/F3 cells, also could not prevent gamma irradiation-induced apoptosis. Although JAK2 is essential for hGM-CSF dependent anti gamma irradiation-induced apoptosis, it appeared that JAK2 does not seem sufficient for the activity.
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PMID:Analysis of mechanisms involved in the prevention of gamma irradiation-induced apoptosis by hGM-CSF. 1069 27

The NF-kappa B transcription factor controls the expression of many genes, including genes regulating cell proliferation or survival and involved in oncogenesis. We showed that many breast cancers express high levels of the NF-kappa B inhibitor p100. In these cells, p100 sequesters NF-kappa B in the cytoplasm and blocks the induction of NF-kappa B-dependent genes in response to stimuli such as TNF-alpha. We also demonstrated that the mechanisms controlling NF-kappa B activity in adenocarcinoma cells differ from those observed in lymphoid cells. Finally, we showed that NF-kappa B was activated in response to chemotherapeutic drugs. However, this activation does not modify p53 induction or the cytotoxic response in the cell lines we have analyzed. Gene therapy is a novel approach for cancer treatment. We evaluated a gene therapy strategy combining a suicide genes and cytokine genes in a model of peritoneal carcinomatosis induced by colorectal cancer cells (DHD/K12 cells). In vitro transduction of the HSV-TK suicide gene in DHD/K12 cells, sensitize them to ganciclovir cytotoxicity. We also obtained a therapeutic effect by in vivo transduction of the TK gene in animals which had developed a peritoneal carcinomatosis. This therapeutic effect was further enhanced by simultaneous administration of genes coding for the IL-12 or GM-CSF cytokines.
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PMID:[NF-kappa B and cancers]. 1099 82

Since the first introduction of gene-marking technology to the clinical field in 1989 by Rosenberg et al, more than 4,000 patients have participated gene therapy clinical trials worldwide. Most of those patients had malignancies. Nearly 90% of clinical trials, however, are still in phase I-II stage, and only 3 protocols are in the phase III stage in early 2000. As current clinical gene therapy protocols are intended essentially to examine the safety and feasibility of the new strategy, more careful and steady steps may be required before these clinical trials really produce clinical benefits. Focused on cancer gene therapy, direct and indirect approaches are undertaken. In the direct approach, HSV-TK, HLA-B7, or p53 tumor suppressor gene therapies are the three major approaches historically. In for the indirect approach, cytokine or adhesion molecule gene-transferred tumor cells or immunocompetent cells are considered to be promising to enhance patients' antitumor immunity. In particular, we have concentrated on developing immuno gene therapy using GM-CSF-transduced autologous tumor cells. We have already recruited three patients with stage IV renal cell cancer. In all patients, peripheral blood T cells were mobilized after vaccination with GM-CSF-transduced tumor cells, and two of the three patients showed the persistence of cytotoxic T cells against autologous tumor cells. Clinically, one patient has been followed up with stable disease for more than one year since the start of vaccination. Further clinical studies are required to obtain conclusive results.
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PMID:[Review of cancer gene therapy]. 1102 77


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