Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In summary, TGF-beta induces cell cycle arrest, at least in part, through down-regulation of cdk4 levels and inhibition of cdk2 activity. Thus both of the kinases thought to be responsible for phosphorylation and inactivation of RB in mid to late G1 are affected by the cytokine. Inhibition of cdk4 synthesis occurs at the translational level, is p53 dependent, and requires the 5' UTR of cdk4. David Beach's laboratory has found that TGF-beta also causes the induction of the cdk4-specific inhibitor p15 (a p16 family member). Thus TGF-beta uses two pathways to regulate cdk4 function: decreasing its expression and inhibiting its function. Mutant p53 confers resistance to TGF-beta by preventing cdk4 down-regulation and overcoming the inhibition of cdk2 activity. Work from the laboratories of both Massague and Roberts has shown that the inhibition of cdk2 brought about by TGF-beta is caused by the cdk inhibitor p27.
 ...
PMID:p53-dependent repression of cdk4 synthesis in transforming growth factor-beta-induced G1 cell cycle arrest. 883 83

The incidence of NHL is greatly increased in HIV-infected individuals. The vast majority are clinically aggressive B cell-derived neoplasms exhibiting BL, IBL, or LCL histology. Approximately 80% arise systemically (nodal and/or extranodal), and the remaining 20% arise as primary CNS lymphomas. A small proportion are body cavity-based lymphomas associated with KSHV infection. Possible factors contributing to lymphoma development include HIV-induced immunosuppression, chronic antigenic stimulation, and cytokine overproduction. These alterations are associated with the development of oligoclonal B-cell expansions. The appearance of NHL is characterized by the presence of a monoclonal B-cell population displaying a variety of genetic lesions, including EBV infection, c-myc gene rearrangement, bcl-6 gene rearrangement, ras gene mutations, and p53 mutations/deletions. The number and type of genetic lesions varies according to the anatomic site and histopathology. In the case of BL, virtually 100% exhibit c-myc gene rearrangements, two thirds display p53 gene mutations, one third contain EBV, and none exhibit bcl-6 gene rearrangements. In contrast, in the case of IBL, virtually 100% contain EBV, 25% display c-myc gene rearrangements, 20% display bcl-6 gene rearrangements, and very few exhibit p53 gene mutations. These findings suggest that more than one pathogenetic mechanism is operational in the development and progression of AIDS-related NHLs. Further work will be necessary to develop a complete understanding of the etiology and pathogenesis of NHL in the setting of HIV infection. AIDS-related NHL remains an important biologic model for investigating the development and progression of high-grade NHLs as well as NHLs that develop in immune-deficient hosts.
 ...
PMID:Etiology and pathogenesis of AIDS-related non--Hodgkin's lymphoma. 888 Jan 98

In a previous report, we observed by light microscopy the extracellular matrix in 51 vulvar squamous carcinomas and found that some tumors has a prominent stromal response in the form of a regional or diffuse zone of extracellular myxoid matrix containing immature collagen and fibroblasts at the tumor-stromal junction. These tumors were associated with clitoral involvement, ulcerative nonexophytic growth pattern, older age groups, poorer survival rate, and more extensive lymph node metastases than when prominent fibromyxoid stromal response (PFSR) was absent. This behavior was demonstrated despite the fact that these tumors were not larger, more deeply invasive, or of higher grade than when PFSR was absent. In the current immunohistochemical study, we examined cytokine, cell adhesion receptor, and tumor suppressor gene expression in 50 vulvar squamous carcinomas using a panel of antibodies to identify any potential role of these proteins in the development of a PFSR. Semiquantification of expression into none, focal (< 25% of cells showing expression), regional (25-50%), and diffuse (> 50%) patterns revealed PFSR to be statistically associated with high CD44, transforming growth factor (TGF) beta 3, and p53 protein expression, but not with fibroblast growth factor, epidermal growth factor, epidermal growth factor receptor, or E-cadherin expression. When expression of CD44 and either stromal or tumor TGF-beta 3 expression was high, i.e., regional or diffuse in distribution, 15 (50%) of 30 cases were associated with PFSR. In contrast, only 1 (7%) of 14 cases was associated with PFSR when expression was high for only one of these two proteins and none of 3 cases was associated with response when expression was low for both proteins (p = 0.005). Furthermore, in cases showing high expression for both TGF-beta 3 and CD44, PFSR was found in 13 (72%) of 18 cases when p53 expression was diffuse compared with 2 (17%) of 12 cases when expression was less (p = 0.01). Since TGF-beta acts mitogenically for fibroblasts and has been shown to be an inhibitor of epithelial cell growth, its high expression in a carcinoma with PFSR would suggest loss of effect on the epithelial component but an intact effect on the stroma. Since CD44 is known to act as a receptor for hyaluronic acid, which is a prominent stromal component and known to play an important role in cell mobility and tumor aggressiveness, its high expression in association with PFSR would suggest a role of CD44 overexpression in altered hyaluronate metabolism with accelerated tumor cell migration and subsequent distal spread. The current study demonstrates that alterations in cytokine and cell adhesion receptor status variably occur in vulvar squamous carcinoma and that such alterations may affect tumor morphology and behavior.
 ...
PMID:Cytokine, cell adhesion receptor, and tumor suppressor gene expression in vulvar squamous carcinoma: correlation with prominent fibromyxoid stromal response. 888 79

Hodgkin's disease (HD) is characterized by the presence of the typical, clonal malignant Hodgkin and Reed-Sternberg (H-RS) cells in a hyperplastic background of normal reactive lymphocytes, plasma cells, histiocytes, neutrophils, eosinophils and stromal cells. The neoplastic nature of HD is based on aggressive clinical progression, presence of the proliferating and atypical H-RS cells, aneuploidy and cellular clonality. Immunophenotypical studies have demonstrated frequent expression of lymphoid "activation markers' including CD15, CD25, CD30, CD40, CD54, CD70, CD71, CD80, CD86 and MHC class II and less frequent expression of T- or B-cell-associated antigens by the neoplastic H-RS cells. The clonality of H-RS cells is demonstrated by clonal EBV integration, clonal cytogenetic abnormalities including p53 mutations and clonal immunoglobulin rearrangements in some HD cases. There is involvement of diverse molecules with oncogenic potential, including presence of viruses (Epstein-Barr virus and human herpes virus-6) and/or oncogenes/tumour suppressor genes (bcl-2/bcl-x, p53/MDM-2, c-myc, c-fms, N-ras, lck). The histopathological presentation and characteristic clinical features of HD correlate with an unbalanced production of multiple cytokines and define HD as a tumour of cytokine-producing cells. The proportion of malignant H-RS cells to reactive cellular components and fibrosis is dependent on the production of particular cytokines and allows subtyping of HD cases. The combined use of immunohistochemical, biochemical and molecular techniques has thus allowed recognition that HD represents more than one clinico-pathological entity with different types of H-RS cells. The defined mechanism for the biological nature, origin and oncogenesis of H-RS cells remains not fully understood, but is susceptible to further analysis using modern technology.
 ...
PMID:Pathophysiology of Hodgkin's disease: functional and molecular aspects. 892 38

Nitric oxide causes apoptotic cell death in RAW 264.7 macrophages. The cellular response to the NO donor S-nitrosoglutathione (GSNO) comprises an apoptotic morphology and DNA fragmentation, which largely depends on the accumulation of the tumor suppressor gene product p53. Pre-treatment of macrophages with LPS, IFN-gamma in the presence of NG-monomethyl-L-arginine (NMMA) imparts resistance to apoptotic cell death, normally elicited by exogenously-supplied GSNO. Similarly, pre-treatment with low-dose GSNO (25-200 microM) conferred resistance from a second exposure to a higher dose of GSNO (1 mM). Protection is comprehended at the level of blocked p53 accumulation. Upregulation of protective mechanisms in response to non-lethal NO concentrations or by LPS, cytokine pre-stimulation may redirect the ability of nitric oxide to upregulate p53 and to initiate macrophage apoptosis, thereby modulating cellular susceptibility towards NO-intoxication.
 ...
PMID:Cytokine and low-level nitric oxide prestimulation block p53 accumulation and apoptosis of RAW 264.7 macrophages. 895 10

The Apo-1/Fas (CD95) antigen is known to be involved in the process of T cell-mediated target cell killing and has recently been shown to be expressed on myeloma cell lines and native malignant plasma cells. Several cytokines have been reported to interfere with spontaneous and even Apo-1/Fas-induced apoptosis, but no attempt has been made yet to investigate these interactions and the possible underlying mechanisms in myeloma cells. Since in myeloma patients Interferon (IFN)-alpha2 displays a profound therapeutic effect in vivo, which is usually attributed to its growth inhibitory and/or immunomodulatory capacity, we set out to study the potential interference of IFN-alpha2 with Apo-1/Fas-induced apoptosis. Contrary to expectations, IFN-alpha2 reduced the degree of apoptosis caused by the treatment of five Apo-1/Fas-sensitive myeloma cell lines with a Fas monoclonal antibody (mAb). Simultaneous application of IFN-alpha2 and Fas mAb was superior to the prolonged (i.e. >8 h) preincubation with the cytokine as far as inhibition of Apo-1/Fas-induced apoptosis was concerned. This effect of IFN-alpha2 was neither explained by a down-regulation of the Apo-1/Fas receptor nor caused by modulation of the expression levels of c-myc, bcl-2-, bcl-xL, bax- or p53 genes. IFN-alpha2 did not alter the Apo-1/Fas-induced activity of Mitogen-activated protein kinase (MAPK) 1 and did not inhibit the Apo-1/Fas-mediated proteolytic cleavage of ADP-ribosyltransferase, a substrate of Interleukin-beta1 converting enzyme (ICE) and homologues. However, activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) mimicked the effects of IFN-alpha2. Furthermore, the bis-indolylmaleimide GF 109203X, a specific inhibitor of PKC, inhibited the effect of PMA as well as that of IFN-alpha2 on Apo-1/Fas-induced apoptosis. These results point to a PKC-dependent mechanism of transient interaction between the intracellular signaling along the IFN-alpha2 and the Apo-1/Fas pathway (downstream of MAPK signaling as well as of ICE homologues), which becomes exhausted by prolonged stimulation with the cytokine. According to our data IFN-alpha2, applied continuously and in high doses resembling the therapeutic situation in vivo, inhibits myeloma growth. However, based on the observed inhibitory effect of IFN-alpha2 on Apo-1/Fas-induced apoptosis, a partial inhibition of the natural immune surveillance on myeloma cells by endogenous IFN-alpha2 present in the bone marrow microenvironment of this malignancy should be investigated.
 ...
PMID:Modulation of Apo-1/Fas (CD95)-induced programmed cell death in myeloma cells by interferon-alpha 2. 897 13

Recently, clinical application of gene technology in oncology and hematology has been markedly advanced. Pathogenesis of leukemic transformation has been thought that it was resulted from cumulation of activation or mutation in oncogenes or onco-suppressor genes. As a matter of fact, many specific chromosomal abnormalities in leukemias have been thought to be due to production of chimeric fusion gene by translocation and activation in some kinds of oncogenes under specific regulatory genes after translocation. In addition to those, inactivation of onco-suppressor genes, such as RB gene or p53 gene, may be also related to leukemogenesis in some leukemias. Laboratory examinations using molecular technology are being necessary for clinical diagnosis and treatment in many hematological disorders. The examinations detecting rearrangement of major BCR or minor BCR in Ph1 positive leukemias, TCR in T cell malignancy, immunoglobulin in B cell malignancy, PML-RAR alpha fusion gene in APL have become routine for diagnosis of some leukemias. Moreover, these examinations are useful for judgement of treatment effects and evaluation of minimal residual diseases. In this paper, we also discuss the usefulness and importance of these technology especially in stem cell transplantation and cytokine therapy, and the future possibility in this technology for gene therapy.
 ...
PMID:[Clinical application of gene technology for diagnosis and treatment of leukemia]. 902 44

Hepatoma Hep3B cell lines stably expressing a temperature-sensitive p53 species (p53-Val-135) displayed a reduced response to interleukin-6 (IL-6) when cultured at the wild-type (wt) p53 temperature (Wang, L., Rayanade, R., Garcia, D., Patel, K., Pan, H., and Sehgal, P. B. (1995) J. Biol. Chem. 270, 23159-23165). We now report that in such cultures IL-6 caused a rapid (20-30 min) and marked loss of cellular immunostaining for STAT3 and STAT5, but not for STAT1. The loss of STAT3 and STAT5 immunostaining was transient (lasted 120 min) and tyrosine kinase-dependent, and even though the loss was blocked by the proteasome inhibitors MG132 and lactacystin it was not accompanied by changes in cellular levels of STAT3 and STAT5 proteins suggesting that IL-6 triggered a rapid masking but not degradation of these transcription factors. STAT3 and STAT5 masking was accompanied by a reduction in IL-6-induced nuclear DNA-binding activity. The data suggest that p53 may influence Jak-STAT signaling through a novel indirect mechanism involving a wt p53-dependent gene product which upon cytokine addition is activated into a "STAT-masking factor" in a proteasome-dependent step.
 ...
PMID:Proteasome- and p53-dependent masking of signal transducer and activator of transcription (STAT) factors. 903 May 16

The incidence of non-Hodgkin's lymphoma is greatly increased in human immunodeficiency virus (HIV)-infected individuals. Most are clinically aggressive B-cell lymphomas exhibiting Burkitt-type, immunoblastic or large-cell morphology. Approximately 80% arise systemically (nodal or extranodal), and the remaining 20% arise in the central nervous system. A small proportion are body cavity-based (primary effusion) lymphomas associated with Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Possible factors contributing to lymphoma development include HIV-induced immunosuppression, chronic antigenic stimulation, and cytokine overproduction. These phenomena are associated with the development of oligoclonal B-cell expansions. The appearance of malignant lymphoma is characterized by the presence of a monoclonal B-cell population displaying a variety of genetic lesions including Epstein-Barr virus (EBV) infections, c-myc gene rearrangement, bcl-6 gene rearrangement, ras gene mutations, and p53 gene mutations/deletions. The number and type of genetic lesions varies according to anatomic site of origin and histopathology. In the case of Burkitt-type lymphoma, virtually 100% exhibit c-myc gene rearrangement, two thirds display p53 gene mutations, one third contain EBV, and none exhibit bcl-6 gene rearrangements. In contrast, in the case of immunoblastic lymphoma, virtually 100% contain EBV, 25% display c-myc gene rearrangements, 20% display bcl-6 gene rearrangements, and few exhibit p53 gene mutations. These findings suggest that more than one pathogenetic mechanism is operational in the development and progression of acquired immunodeficiency syndrome (AIDS)-related lymphoma. Further work is necessary to develop a thorough understanding of the origin and pathogenesis of malignant lymphoma in the setting of HIV infection. AIDS-related lymphoma remains an important biologic model for investigating the development and progression of high-grade non-Hodgkin lymphomas as well as malignant lymphomas that develop in immune-deficient hosts.
 ...
PMID:Molecular pathology of acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma. 904 11

Gene therapy as an anti-tumor strategy is becoming a powerful tool for cytokine delivery to inhibit the growth of many tumors. Several delivery systems are being utilized and designed for the expression of specific genes to achieve a therapeutic result. Liposomes, retroviral vectors, and adenoviral vectors have all been used and eventual clinical application may depend on the type of tumor, the location, the specific gene carried, and the patient's health status. Novel expression vectors may eventually achieve tissue-specific targeting and low immuno-reactivity. Inactivation of mutated oncogenes, such as ras, or re-expression of inactive suppressor genes, such as p53 have been used as strategies for anti-tumor therapy. Additionally, exogenious genes, such as viral thymidine kinase that metabolize chemotherapeutic agents to achieve local cytotoxicity have also been employed. Neuro-endocrine tumors are targets of these gentic strategies since they are often difficult to treat by conventional methods because of their location (brain tumors) or because they have spread from the primary tumor (melanoma). Further advances in the design of these vectors may achieve safe targeting of a variety of malignant tumors.
 ...
PMID:Anti-tumor gene therapy. 904 51


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>