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)

Baxalpha was isolated due to its interaction with Bcl-2. Baxalpha overexpression in an interleukin (IL)-3 dependent cell line accelerates apoptosis upon removal of the cytokine. The ratio of Baxalpha to Bcl-2 appears to be crucial for the effect. To study the action of the bax gene product in vivo, we have generated transgenic mice overexpressing Baxalpha specifically in T cells. Such T cells show accelerated apoptosis in response to gamma-radiation, dexamethasone and etoposide. By crossing baxalpha mice with bcl-2 transgenics we show that the critical nature of the Baxalpha:Bcl-2 ratio holds in primary T cells and that it can be manipulated to elicit a strong response to previously resisted stimuli. p53 has a role in the regulation of apoptosis in response to DNA-damaging agents. p53 directly activates transcription of the bax gene. The presence of the baxalpha transgene accelerated apoptosis in thymocytes from both p53-l- and p53+l- mice in response to dexamethasone. Thymocytes from p53-l- mice with the baxalpha transgene showed similar resistance to apoptosis by DNA-damaging agents as did p53-l- mice without the transgene. Baxalpha overexpression alone cannot restore the DNA damage apoptosis pathway, suggesting that p53 is required to induce or activate other factor(s) to reconstitute the response fully.
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PMID:T cells from baxalpha transgenic mice show accelerated apoptosis in response to stimuli but do not show restored DNA damage-induced cell death in the absence of p53. 863 54

Hematopoiesis gives rise to blood cells of different lineages throughout normal life. Abnormalities in this developmental program lead to blood cell diseases including leukemia. The establishment of a cell culture system for the clonal development of hematopoietic cells made it possible to discover proteins that regulate cell viability, multiplication and differentiation of different hematopoietic cell lineages, and the molecular basis of normal and abnormal blood cell development. These regulators include cytokines now called colony-stimulating factors (CSFs) and interleukins (ILs). There is a network of cytokine interactions, which has positive regulators such as CSFs and ILs and negative regulators such as transforming growth factor beta and tumor necrosis factor (TNF). This multigene cytokine network provides flexibility depending on which part of the network is activated and allows amplification of response to a particular stimulus. Malignancy can be suppressed in certain types of leukemic cells by inducing differentiation with cytokines that regulate normal hematopoiesis or with other compounds that use alternative differentiation pathways. This created the basis for the clinical use of differentiation therapy. The suppression of malignancy by inducing differentiation can bypass genetic abnormalities that give rise to malignancy. Different CSFs and ILs suppress programmed cell death (apoptosis) and induce cell multiplication and differentiation, and these processes of development are separately regulated. The same cytokines suppress apoptosis in normal and leukemic cells, including apoptosis induced by irradiation and cytotoxic cancer chemotherapeutic compounds. An excess of cytokines can increase leukemic cell resistance to cytotoxic therapy. The tumor suppressor gene wild-type p53 induces apoptosis that can also be suppressed by cytokines. The oncogene mutant p53 suppresses apoptosis. Hematopoietic cytokines such as granulocyte CSF are now used clinically to correct defects in hematopoiesis, including repair of chemotherapy-associated suppression of normal hematopoiesis in cancer patients, stimulation of normal granulocyte development in patients with infantile congenital agranulocytosis, and increase of hematopoietic precursors for blood cell transplantation. Treatments that decrease the level of apoptosis-suppressing cytokines and downregulate expression of mutant p53 and other apoptosis suppressing genes in cancer cells could improve cytotoxic cancer therapy. The basic studies on hematopoiesis and leukemia have thus provided new approaches to therapy.
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PMID:The control of hematopoiesis and leukemia: from basic biology to the clinic. 864 73

Mammary epithelial cells (MECs) were isolated and cultured from mammary glands of healthy women undergoing reduction mammoplasty. Normal MECs were infected with the transforming hybrid virus adeno-5/SV40. Two transformed epithelial cell lines, M1 and M2, were obtained, characterised phenotypically and studied for the production of and the response to cytokines and growth regulators. In both cell lines, expression of the SV40 large T antigen was associated with loss of interleukin 6 (IL-6) production and responsiveness as well as with down-regulation of IL-8 and transforming growth factor (TGF)-alpha production. Both M1 and M2 cell lines were capable of forming colonies in semisolid media, but upon injection into severe combined immunodeficient (SCID) mice only M2 cells were tumorigenic. DNA synthesis in M1 cells was partially inhibited by serum or TNF-alpha and weakly stimulated by hydrocortisone (HC) and IL-8. In contrast, M2 cells were totally unresponsive to a variety of growth regulators. Both lines overexpressed the p53 protein at levels about 20-fold higher than those observed in primary MEC cultures, but no mutations of the p53 gene could be detected. The date confirm the view that the expression in human mammary cells of different oncogenes - including the SV40 T antigen - is frequently associated with alterations of cytokine production and responsiveness.
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PMID:Defective interleukin six expression and responsiveness in human mammary cells transformed by an adeno 5/SV40 hybrid virus. 864 79

Antitumor CTL responses were studied in a model tumor hearing a mutant human p53 gene. We found ineffective induction of antitumor CTL in mice bearing these tumors associated with measurable defects in the function of dendritic cells (DC) from these animals. In this study we investigate the mechanism of this defect in mature DC and find that functional DC can be generated by growth from the bone marrow of tumor-hearing animals. Tumor cell supernatants did not affect the function of mature DC obtained from the spleen of tumor-bearing animals, but significantly suppressed the ability to generate functional DC from the bone marrow of control mice in vitro. This suggests that tumor cells may release factors which block early stages of DC maturation from precursors. DC generated from the bone marrow of tumor-bearing mice showed normal potential to stimulate allogeneic T cells, to stimulate anti-mutant p53 peptide-specific cytotoxic T cells, and to induce anti-p53 CTL responses in vivo in control mice. Repeated immunization with peptide-pulsed DC generated from the bone marrow of control mice (every 4-5 days) blocked progression of established tumors. Immunization of mice with peptide-pulsed DC obtained from the spleen of tumor-bearing mice (4 weeks after tumor injection) did not affect the tumor growth, whereas immunization with peptide-pulsed DC generated from bone marrow of tumor-bearing mice resulted in significantly prolonged survival and delayed tumor growth. Tumor progression was associated with change of the balance Th1/Th2 cells in favor of the Th2-like cytokine profile, while effective immunization was associated with a shift to the Th1 phenotype. Thus, frequent immunization of mice with mutant p53 peptide-pulsed DC generated from stem cells of tumor-bearing hosts can induce effective antitumor CTL responses associated with production of Th1 cells and lead to significant antitumor effects.
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PMID:Dendritic cells in antitumor immune responses. II. Dendritic cells grown from bone marrow precursors, but not mature DC from tumor-bearing mice, are effective antigen carriers in the therapy of established tumors. 866 91

Hematopoietic cells require certain cytokines including colony-stimulating factors and interleukins to maintain viability. Without these cytokines the program of apoptotic cell death is activated. Cells from many myeloid leukemias require cytokines for viability, and apoptosis is also activated in these leukemic cells after cytokine withdrawal resulting in reduced leukemogenicity. The same cytokines protect normal and leukemic cells from induction of apoptosis by irradiation and cytotoxic chemotherapeutic compounds. This suggests that decreasing the levels of viability inducing cytokines may increase the effectiveness of cytotoxic anti-cancer therapy. The susceptibility of normal and cancer cells to induction of apoptosis is also regulated by the balance between apoptosis-inducing genes such as the tumor suppressor wild-type p53, and c-myc and bax, and apoptosis-suppressing genes such as the oncogene mutant p53, and bcl-2 and bcl-XL. Cell susceptibility to induction of apoptosis in leukemic cells could be enhanced by increased expression of apoptosis-inducing genes and/or decreased expression of apoptosis-suppressing genes. Modulation of expression of apoptosis-regulating genes should thus also be useful for improvement of anti-cancer therapy.
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PMID:Control of apoptosis in hematopoiesis and leukemia by cytokines, tumor suppressor and oncogenes. 866 46

AIDS-related non-Hodgkin's lymphomas (AIDS-NHLs) are almost invariably derived from B cells and are grouped into three distinct histologic categories, including small-non-cleaved-cell lymphoma (SNCCL), diffuse large-cell lymphoma (DLCL), and anaplastic large-cell lymphoma (ALCL). In addition, AIDS-NHLs presenting solely as a body cavity effusion are thought to be a peculiar clinicopathologic entity and are defined as body-cavity-based lymphoma (BCBL). At the biologic level, AIDS-related lymphomagenesis is characterized by activation of proto-oncogenes, inactivation of tumor suppressor genes, viral infection of the tumor clone, and deregulated cytokine production. Distinct AIDS-NHL types associate with specific molecular pathways. The first pathogenetic pathway clusters with AIDS-SNCCL, and is characterized by a relatively mild degree of host immunodeficiency. AIDS-SNCCL consistently associates with c-myc rearrangements and p53 inactivation in 100 and 60% of cases, respectively, whereas infection by Epstein-Barr virus (EBV) is restricted to 30% of the cases. Production of high levels of interleukin-10 is an additional peculiar feature of EBV-positive AIDS-SNCCL. The second pathogenetic pathway associates with AIDS-DLCL, which is usually accompanied by marked host immunodeficiency. AIDS-DLCL is characterized by EBV infection in the large majority of cases and by the mutually exclusive presence of bcl-6 rearrangements and c-myc translocations in 40% of the cases. A third pathway characterizes AIDS-BCBL, which associates in virtually all cases with infection by EBV and with the presence of DNA sequences of the recently identified Kaposi sarcoma herpesvirus in the apparent absence of other known genetic lesions. Finally, the pathogenetic features of AIDS-ALCL are still under investigation.
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PMID:AIDS-related non-Hodgkin's lymphomas: molecular genetics, viral infection and cytokine deregulation. 867 42

The tumor suppressor p53 plays a central role in negative growth control, including growth arrest and apoptosis. Interferons (IFNs) are capable of modulating a variety of cellular responses, including apoptosis. In this study, we have evaluated the influence of gamma- and alpha-interferon (IFN) on wild-type (wt) p53-induced apoptosis using a Burkitt lymphoma cell line, BL41, transfected with a temperature-sensitive p53 construct, gamma-IFN, but not alpha-IFN, was found to protect cells from wt p53-induced apoptosis. The gamma-IFN-dependent protection was due neither to down-regulation of p53, nor to the p53-induced genes, p21 (WAF-1) and bax, nor to up-regulation of bcl-2 or bcl-xL. Expression of the proto-oncogene c-myc, implicated in the control of both proliferation and apoptosis, was not affected by gamma-IFN. We conclude that gamma-IFN can suppress p53-induced apoptosis, and that the cytokine microenvironment may be decisive in the cellular response to wt p53 expression.
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PMID:Wild-type p53-induced apoptosis in a Burkitt lymphoma cell line is inhibited by interferon gamma. 869 May 9

The concept that lymphomagenesis is a multistep process is now widely accepted. Various factors are involved in the development and malignant progression of B-cell lymphoproliferative disorders. The most frequently recognized alterations in these disorders are chromosomal translocations which lead to the activation of proto-oncogenes (c-myc) or genes encoding for proteins involved in the control of the cell cycle (cyclin D1), differentiation (bcl-6) and apoptosis (bcl-2). In addition, genetic changes that inactivate tumor suppressor genes (p53, Rb, p16) have recently been identified. Infectious agents may also play a role in lymphomagenesis either by directly driving B-cell proliferation (EBV) or by inducing a chronic antigenic stimulation (EBV, HCV, HBV, helicobacter pylori). Finally, several data indicate that local cytokine networks and, in particular, autocrine (IL-6, IL-10) and/or paracrine (IL-2, IL-4, IL-6) loops probably play a contributory role in the development and evolution of B-cell lymphoproliferation. In the last few years, the advent of molecular biology techniques has allowed important advances in the definition of the events involved i the earlier phases of lymphoma development. This has been made possible, in particular, by the study of a series of oligoclonal or monoclonal lymphoproliferative disorders characterized by an indolent or "smoldering" clinical course, such as follicular lymphoma and the lymphoproliferation associated with autoimmune diseases, which are at high risk of evolution to a highly malignant lymphoma. In nearly all of these conditions, the clonal B-cells responsible for the early stages of the disease are probably not fully transformed and retain various degrees of responsiveness to a wide variety of microenvironmental stimuli (antigen or autoantigen stimulation, interactions with "reactive" T lymphocytes, local cytokine networks). These latter in turn may induce the regression of pathological lesions, maintain the disease in an active state or contribute to the evolution towards an overtly malignant lymphoma. These findings open new avenues for the design of unconventional strategies of intervention aimed at preventing the malignant evolution of pre-lymphomatous lesions and controlling the clinical course of certain low-grade B-cell lymphomas.
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PMID:Cellular and molecular bases of B-cell clonal expansions. 872 94

Uncontrolled proliferation of epidermal cells is the most prominent characteristic of psoriasis. This widespread skin disease can be effectively treated with the microbial substance FK506, which acts by modulating gene expression. We, therefore, asked if the drug changes the expression of genes involved in growth regulation (the mitogenic cytokine interleukin-8 (IL-8) and p53, a negative cell cycle regulator) and signal transduction (protooncogenes c-ras, c-raf, and HER-2). Gene expression was monitored by semiquantitative mRNA-PCR and for p53 by immunocytochemistry in cultured primary keratinocytes (KC). In addition, p53 expression was analysed in skin biopsies of psoriatic patients. After 1-3 hr, IL-8 mRNA levels were dose-dependently decreased in tacrolimus (FK506)-treated cells. Protooncogene expression was not significantly altered. Interestingly, p53 transcription was clearly induced by FK506 treatment. This tendency could be verified on the protein level by immunocytochemistry. In contrast, p53 expression was decreased in lesional psoriatic as compared to normal skin, providing evidence that not only posttranslational modification of the p53 protein, but also transcriptional modulation of the p53 gene, are involved in pathological processes and pharmacological drug action in skin. Together with earlier results showing downmodulation for IL-8 receptor type A expression in cultured KC treated with FK506, these results suggest that both the mitogenic IL-8/IL-8R system and the cell cycle inhibitor p53 represent potential targets for the antipsoriatic action of the drug, whereas protooncogenes acting downstream in mitogenic signal transduction cascades are unaffected. The differential modulation of an entire set of genes provides evidence for the specificity of the drug effects and rules out nonspecific toxic effects on KC.
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PMID:Antioncogene P53 and mitogenic cytokine interleukin-8 aberrantly expressed in psoriatic skin are inversely regulated by the antipsoriatic drug tacrolimus (FK506). 878 47

Apoptosis induced by wild-type p53 or cytotoxic compounds in myeloid leukemic cells can be inhibited by the cytokines interleukin 6, interleukin 3, granulocyte-macrophage colony-stimulating factor, and interferon gamma and by antioxidants. The antioxidants and cytokines showed a cooperative protective effect against induction of apoptosis. Cells with a higher intrinsic level of peroxide production showed a higher sensitivity to induction of apoptosis and required a higher cytokine concentration to inhibit apoptosis. Decreasing the intrinsic oxidative stress in cells by antioxidants thus inhibited apoptosis, whereas increasing this intrinsic stress by adding H2O2 enhanced apoptosis. Induction of apoptosis by wild-type p53 was not preceded by increased peroxide production or lipid peroxidation and the protective effect of cytokines was not associated with a decrease in these properties. The results indicate that the intrinsic degree of oxidative stress can regulate cell susceptibility to wild-type p53-dependent and p53-independent induction of apoptosis and the ability of cytokines to protect cells against apoptosis.
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PMID:Cellular oxidative stress and the control of apoptosis by wild-type p53, cytotoxic compounds, and cytokines. 879 72


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