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)

Locoregional human IFN-gamma may have activity against refractory ovarian cancer. We investigated this further in an ovarian cancer xenograft model. Administered at clinically relevant doses, intraperitoneal IFN-gamma prolonged the survival of mice bearing multiple established peritoneal tumours, with optimal treatment giving a 3-6-fold increase in median survival time. Daily dosing, which was superior to intermittent treatment, decreased DNA synthesis and induced apoptosis in tumour cells with maximal effects after 7-21 days treatment. This was preceded by an increase in p53 protein at 48 h. The effect of IFN-gamma was not enhanced by sequential treatment with carboplatin. However, the matrix metalloprotease inhibitor, batimastat, further increased mouse survival when given after IFN-gamma. Thus IFN-gamma is cytotoxic to ovarian epithelial cells in vivo and intensive locoregional dosing over short periods is effective. Sequential administration of novel agents that perturb the host/tumour relationship may be of benefit.
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PMID:Interferon gamma induces cell cycle arrest and apoptosis in a model of ovarian cancer: enhancement of effect by batimastat. 937 92

The chronic skin disease psoriasis is characterized by epidermal hyperproliferation and inflammation. The exact etiology of the disease is still unknown. At the molecular level, overexpression of growth factors and proinflammatory cytokines such as IL-8 and the corresponding receptor has been described in psoriatic plaques. On the other hand, the loss of inhibitory control mechanisms is involved in the pathogenesis of the disease, as exemplified by the reduced mRNA levels for the cell cycle inhibitor p53 found in lesional skin. Here we extend these findings to a cytokine with negative regulatory functions, IL-10. Only under certain conditions are human keratinocytes able to synthesize IL-10. In skin, pathological overexpression of IL-10 was described om atopic dermatitis. IL-10 exerts its effects via a specific receptor (IL-10R). We show here for the first time the presence and functionality of IL-10R in epidermal cells and its dramatically decreased expression in acute exanthematic psoriatic epidermis by in vitro and in situ binding studies. These results were substantiated using semiquantitative reverse transcriptase-PCR, demonstrating decreased expression of the IL-10R gene in psoriatic skin, its down-modulation by the proinflammatory cytokine IL-8, and its pharmacological induction in cultured cells. Biological responsiveness of epidermal cells toward IL-10 could also be demonstrated by a reduction of the growth rate and inhibition of IFN-gamma-induced HLA-DR expression. Our results provide the first evidence for a role of the IL-10R gene in the homeostasis of the epidermis and substantiate the concept of a loss of negative regulatory peptides as a step in the eruption of psoriasis.
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PMID:Demonstration and functional analysis of IL-10 receptors in human epidermal cells: decreased expression in psoriatic skin, down-modulation by IL-8, and up-regulation by an antipsoriatic glucocorticosteroid in normal cultured keratinocytes. 955 Apr 34

Previously we demonstrated that IFN-alpha augments mda-6/WAF1 and inhibits cyclin-dependent kinases in a p53-independent fashion in B 16 murine melanoma cells. On the other hand, IFN-gamma activates p53 expression without affecting the mda-6/WAF1 system. Combination of the two IFNs is additive. B16 cells acquire IFN-alpha resistant but IFN-gamma sensitive phenotype after long term IFN-alpha treatment (B16alpha cells). Here we demonstrate the absence of mda-6/WAF1-associated repression of cyclin-dependent kinases, but the existence of p53-dependent c-myc inhibition in IFN-gamma-treated B16alpha cells. Clearly, selective desensitization of IFN-alpha related growth regulation does not influence the IFN-gamma associated pathway. Our results further support the coexistence of distinct growth regulatory mechanisms in B16 cells that can be activated by different IFN-types independently of each other.
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PMID:Lack of mda-6/WAF1/CIP1-mediated inhibition of cyclin-dependent kinases in interferon-alpha resistant murine B16 melanoma cells. 957 Mar 77

Cathepsin D (CD), the major intracellular aspartyl protease, is a mediator of IFN-gamma and TNF-alpha induced apoptosis. Using subtractive hybridization screening we isolated CD as an upregulated transcript in PA1 human ovarian cancer cells undergoing adriamycin-induced apoptosis. CD mRNA levels increased in wild-type p53-expressing PA1, ML1 leukemia and U1752 lung cancer cells but not in mutant p53-expressing cells following adriamycin exposure. Overexpression of CD inhibited growth of colon, liver, and ovarian cancer cells. CD protein expression was increased by exposure of ML1 cells to etoposide, adriamycin or gamma-radiation. Inhibition of CD protease with Pepstatin A suppressed p53-dependent apoptosis in lymphoid cells, suggesting a possible role for CD in p53-dependent cell death. CD-/- fibroblasts were found to be more resistant to killing by adriamycin and etoposide, as compared to CD+/+ cells. Two p53 DNA-binding sites located in the CD-promoter specifically bound to p53 protein in vitro and appeared to mediate transactivation of a CD-promoter luciferase-reporter during p53-dependent apoptosis. These observations link CD protease to p53-dependent tumor suppression and chemosensitivity.
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PMID:Potential role for cathepsin D in p53-dependent tumor suppression and chemosensitivity. 961 26

p53 is a tumor suppressor which exerts its function through the regulation of genes mediating cell cycle arrest and the induction of apoptosis. Cellular survival and proliferation can be positively regulated through the action of cytokines. These signals act through the activation of cell surface receptors, and the phosphorylation of intracellular signaling components, e.g. members of the Stat family (signal transducers and activators of transcription). The signaling effects of p53 and the cytokine receptors on the cellular phenotype are counteracting. We investigated the influence of p53 on the transactivation potential of Stat5. p53 repressed the prolactin induction of the Stat5 mediated transcription of the beta-casein promoter-luciferase reporter gene, but did not affect IFN-gamma induced, Stat1 dependent transcription of the IRF-1 promoter. The inhibition was not due to a decrease in the cellular concentration of Stat5 or to interference with its specific DNA binding activity. No repression of the basal transcriptional activity of the beta-casein promoter was observed. p53 mutants defective in their DNA binding or oligomerization functions had only weak inhibitory effects, but a mutant of p53 in the transactivation domain, efficiently repressed Stat5 dependent induction. The repressive function of p53 on Stat5 activity is independent of the amino-terminal transactivation domain, but requires a functional DNA binding domain and the carboxyl-terminal domain. Our experiments show that p53 counteracts Stat5 mediated cytokine induction of gene transcription. The effect is specific for Stat5 and independent of p53 induced apoptosis.
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PMID:p53 suppresses cytokine induced, Stat5 mediated activation of transcription. 980 59

IFN-gamma induces cell cycle arrest and p53-independent apoptosis in primary cultured hepatocytes. However, it is not yet understood what molecules regulate the mechanism. We report here that interferon regulatory factor 1 (IRF-1) is an essential molecule in these phenomena. Hepatocytes from IRF-1-deficient mice were completely resistant to IFN-gamma in apoptosis indicated by three different hallmarks such as LDH release, DNA fragmentation and the activation of caspase-3 family. Caspase-1 expression was little detected in hepatocytes, and constitutive and IFN-gamma-induced mRNA expression of Fas or caspase-3 did not change in between wild type and IRF-1-deficient hepatocytes. Expression of IFN-gamma-inducible caspase, caspase-11, did not change either. Thus, it is unlikely that these molecules directly regulate the mechanisms. Interestingly, IRF-1-deficient hepatocytes were also resistant to IFN-gamma-induced cell cycle arrest despite IFN-gamma-induced cell cycle arrest and apoptosis are regulated by independent pathways. Results by Northern blot analysis showed that IFN-gamma-induced but not constitutive p53 mRNA expression was regulated by IRF-1. In fact, IFN-gamma did not induce cell cycle arrest in p53-deficient hepatocytes. Taken together, IRF-1 mediates IFN-gamma signaling into primary hepatocytes for cell cycle arrest via p53 expression and for apoptosis.
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PMID:IRF-1 is an essential mediator in IFN-gamma-induced cell cycle arrest and apoptosis of primary cultured hepatocytes. 1020 42

The relationship between nitric oxide synthase II (NOS II) inducibility and the metastatic ability of UV-2237 murine fibrosarcoma cells was determined. Highly metastatic cells survived to produce numerous lung metastases after i.v. injection in syngeneic C3H/HeN mice, whereas poorly metastatic cells did not. Highly metastatic clones exhibited higher levels of NOS II than did poorly metastatic clones in response to interleukin 1alpha and IFN-gamma stimulation. Furthermore, both poorly and highly metastatic clones contained an identical p53 mutation. Overexpression of NOS II in a highly metastatic clone by transfection with NOS II gene retarded tumor growth and completely suppressed metastasis. Our data indicate that a low to moderate level of NOS II expression directly correlates with metastatic ability of UV-2237 fibrosarcoma cells carrying mutant p53 and that a high level of nitric oxide production suppresses tumor growth and metastasis.
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PMID:Direct correlation between nitric oxide synthase II inducibility and metastatic ability of UV-2237 murine fibrosarcoma cells carrying mutant p53. 1023 90

Pancreatic cancer is a deadly disease challenging basic and clinical researchers alike in characterizing its pathobiology and finding better treatment options. A number of molecular alterations including gene mutations such as k-ras, p53, and Smad4 and aberrant expression of a variety of genes have been identified in recent years. This review focuses on two families of growth factors and growth factor receptors which are representative for the molecular alterations observed in pancreatic cancer: the transforming growth factor-beta superfamily of serine-threonine kinase receptors and their ligands, which usually act as negative growth regulators, and the epidermal growth factor receptor family and their ligands, which have the potential to act as growth promoters in pancreatic cancer. In addition, we will discuss the role of the cytokines TNF-alpha, IFN-gamma, and IL-6 and its effects on pancreatic cancer cell proliferation in vitro and in vivo. Pancreatic cancer cell biology consists of complex interactions of various factors, and a better understanding of the molecular pathogenesis of this disorder might lead to better treatment strategies in the near future.
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PMID:Growth factors and cytokines in pancreatic carcinogenesis. 1041 56

Our laboratory has recently developed a lipopolyplex consisting of DOTAP:cholesterol liposomes, protamine sulfate, and plasmid DNA (LPD) that provides improved systemic gene delivery compared with lipoplex following tail vein injection in mice. Because endothelial cells are the primary cells transfected in the lung, it was hypothesized that LPD might be an effective vector for gene therapy of pulmonary metastases. This hypothesis was examined by testing the efficacy of cytokine (IL-12) and tumor suppressor (p53) strategies for treatment of an experimental model of pulmonary metastasis in C57Bl/6 mice. Surprisingly, all LPD complexes including those containing an 'empty' plasmid provided a potent (>50% inhibition) and dose-dependent antitumor effect, compared with dextrose-treated controls. In addition, i.v. injections of LPD containing 'empty' plasmid also inhibited tumor growth in a subcutaneous model of C3 fibrosarcomma. The antitumor effect correlated well with a strong and rapid proinflammatory cytokine (TNF-alpha, IL-12 and IFN-gamma) response. Naked plasmid DNA did not elicit a cytokine response and the response required assembly of DNA into a lipoplex or the LPD lipopolyplex. Except for the heart, elevated levels of cytokine were observed in all organs (lung, liver, kidney and spleen) where LPD is known to have gene transfer activity. Methylation of immune-stimulatory CpG motifs in the plasmid component of LPD inhibited the proinflammatory cytokine response as well as the antitumor effect of LPD in both tumor systems. This suggests that i. v. administration of LPD elicits a systemic proinflammatory cytokine response that mediates the antitumor activity of the lipopolyplex. In addition, the antitumor activity was not observed in SCID mice suggesting a possible role for B or T lymphocytes in the antitumor response initiated by LPD. This represents the first demonstration that an intravenously administered cationic liposome-based nonviral vector can promote a systemic, Th1-like innate immune response. The immune adjuvant properties of LPD might prove to be suitable for delivering tumor-specific antigens in the context of DNA vaccination.
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PMID:LPD lipopolyplex initiates a potent cytokine response and inhibits tumor growth. 1060 82

Interferons (IFN) inhibit the growth of tumor cells by blocking the progression of their cell cycle. Recently, we showed that this cell cycle inhibition correlates with the ability of IFN to upregulate the cyclin-dependent kinase inhibitor p21(WAF1). This, however, is not proof of a causal relationship. Using p21(WAF1)-deficient cells derived from the HCT116 colon adenocarcinoma cell line, we now show that p21(WAF1) is indeed responsible for the antiproliferative effects of the type II IFN, IFN-gamma. IFN-gamma upregulated p21(WAF1) expression in a p53-independent manner, decreased cyclin-dependent kinase 2 activity, and inhibited entry into the S phase of the cell cycle in p21+/+ but not in p21-/- HCT116 cells. We additionally found that the lack of p21(WAF1) expression resulted in an increase in the ability of IFN-gamma to induce apoptosis, as reflected by an earlier induction of DNA fragmentation and caspase 3 activity in p21-/- cell. Our results indicate that p21(WAF1) expression is necessary for IFN-gamma-mediated cell cycle inhibition and suppression of IFN-gamma-induced apoptosis.
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PMID:IFN-gamma induction of p21(WAF1) is required for cell cycle inhibition and suppression of apoptosis. 1063 4


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