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)

Biologic responses to cytokines are mediated by intracellular pathways involving induction of signaling and metabolic cascades. Interferon (IFN) regulatory factor-1 (IRF-1) is a major transcription factor induced not only by IFN-gamma but also by other cytokines including tumor necrosis factor-alpha (TNF-alpha). Possible IRF-1 binding sequence elements have been located in the promoter regions of several genes, including p53, inducible nitric oxide synthase, and cyclin D1. IFN-gamma and TNF-alpha can inhibit hematopoiesis in vitro and have been implicated in the pathophysiology of bone marrow (BM) failure. We investigated whether the inhibitory effects of these cytokines were intracellularly mediated through the expression of IRF-1 or -2 in target cells. In total BM cells, IRF-1 mRNA expression increased after stimulation with IFN-gamma and TNF-alpha; the stronger effect was observed with IFN-gamma. In contrast, IRF-2 mRNA expression was constitutive and not altered by cytokine stimulation. By gene amplification, low levels of IRF-1 mRNA were present in unstimulated, highly purified CD34+ cells; on exposure to IFN-gamma and TNF-alpha, amplified IRF-1 mRNA showed a much stronger signal than control. When CD34+ cells were treated with IFN-gamma and TNF-alpha, IRF-1 antisense oligodeoxynucleotide (ODN) partially reversed the suppressive effects on CD34+ cell-derived colony formation by IFN-gamma but not those by TNF-alpha. In parallel experiments, IRF-1 antisense ODN decreased both IRF-1 protein and mRNA expression. The effects of ODN were sequence-specific and concentration-dependent. These results suggest that the inhibitory hematopoietic effects of IFN-gamma and TNF-alpha are mediated by different pathways. For IFN-gamma, IRF-1 is involved in the activation of cellular genes responsible for IFN-gamma suppressive effects.
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PMID:Hematopoietic inhibition by interferon-gamma is partially mediated through interferon regulatory factor-1. 757 40

The p53 tumor suppressor gene plays a role in controlling a G1 phase checkpoint. The WAF1/CIP1 gene with encodes p21WAF1/CIP1 protein, an inhibitor of cyclin-dependent kinases, is a downstream mediator of p53 function. We examined expression of the WAF1/CIP1 gene and its relationship to growth arrest and differentiation in p53-null human leukemic cell lines. We show that p53-independent induction of WAF1/CIP1 occurs in human leukemia cells treated with 12-O-tetradecanoylphorbol-13-acetate, okadaic acid, or IFN-gamma but not with retinoic acid, vitamin D3, or DMSO. Furthermore, WAF1/CIP1 induction correlates with growth arrest associated with monocyte-macrophage differentiation. The present studies support the idea that WAF1/CIP1 gene expression can be regulated through multiple mechanisms, suggesting that strategies may be designed to restore the G1 checkpoint controls in p53-null cells by targeting these p53-independent mechanisms of WAF1/CIP1 induction.
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PMID:p53-independent induction of WAF1/CIP1 in human leukemia cells is correlated with growth arrest accompanying monocyte/macrophage differentiation. 783 38

Regulation of apoptosis (programmed cell death) is critical for maintaining tissue homeostasis. Recent studies indicate a tight coupling between cellular proliferation and apoptosis as cell cycle regulators such as Cyclin D, E1A and E7 appear to influence both events. Each of these modulators is able to bind to and inhibit the function of the retinoblastoma tumor suppressor protein (RB). RB functions, in part, by binding to and inactivating E2F transcription factors, preventing expression of E2F-activated genes associated with G1/S cell-cycle progression. Loss of functional RB deregulates E2F activity and, depending on cell type and environmental factors, promotes tumorigenesis or apoptotic death. To determine the effect of RB on IFN-gamma induced apoptosis, we treated RB-defective carcinoma cell lines and their respective RB-constituted sister clones with IFN-gamma and examined the cells for alterations characteristic of apoptosis. We observed that RB-defective cells, but not the RB-reconstituted clones, decreased in size following IFN-gamma treatment. IFN-gamma treatment caused increased cell detachment in the RB-defective lines but did not affect adherence of the RB-reconstituted clones. Assays for DNA fragmentation revealed lower molecular weight DNA and the apoptosis-associated oligo-nucleosomal ladder following IFN-gamma treatment of the RB-defective cells while higher molecular weight DNA was present in the IFN-gamma treated, RB-reconstituted lines. IFN gamma-induced apoptosis in RB-defective cells was enhanced by serum stimulation, which is also characteristic of p53-dependent E2F-1-mediated apoptosis. However, IFN-gamma induced apoptosis in RB-defective lines does not require wild-type p53 suggesting that, upon IFN-gamma induction, deregulated E2F-mediated apoptosis can also proceed via p53-independent pathways.
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PMID:Retinoblastoma protein inhibits IFN-gamma induced apoptosis. 862 2

To gain mechanistic insights into the growth control of renal cell carcinoma cells by IFN-gamma and TGF-beta, a recently established human renal carcinoma TC-1 cell line was treated with different concentrations of IFN-gamma and TGF-beta. Cell growth and changes in specific gene expression were evaluated. IFN-gamma exerted an antimitogenic effect on TC-1 cells, whereas TGF-beta was essentially without effect. The growth-suppressed cells had reduced expression of proliferating cell nuclear antigen (PCNA), the G2/M cell cycle transition regulatory proteins cyclin B/p34cdc2, the tumor suppressor gene pRB, and the antimetastatic gene nm23. However, levels of other cell cycle regulatory protein molecules such as cyclin D and p53 were unaffected by IFN-gamma. Thus, the antimitogenic effect of IFN-gamma may be mediated by its ability to modulate specific oncogene changes.
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PMID:Control of renal carcinoma TC-1 growth, cyclin/kinase and nm23 expression by IFN-gamma and TGF-beta. 871 96

Mice infected with Friend Leukemia Virus (FLV) rapidly develop erythroleukemia and severe immune deficiency which resembles human AIDS. We have reported that mice infected with a lethal dose of FLV can be 100% cured by 150 cGy total body irradiation (TBI). This curative effect was associated with restoration of cellular immunity which was compromised by the virus. This restoration may result from activation of the IFN-gamma system and IL-2 production. Our research work further demonstrated that no spleen focus-forming virus (SFFV) specific mRNAs, no 6.0kb SFFV fragments and SFFV envelope glycoproteins were detectable in FLV-infected mice treated with low dose TBI. Predicated on our report, del Regato has initiated clinical trials to treat AIDS patients with low dose TBI. The preliminary results are encouraging and the study is continuing. We have also studied the effects of low dose TBI on the expression of the P53 gene. The results show loss or inactivation of P53 tumor suppressor genes in FLV-infected mice, but P53 expression was restored in FLV-infected mice treated by low dose TBI. It is intriguing to speculate that in the curative effect of low dose TBI on mice infected with retrovirus, the P53 tumor suppressor gene may play an important role. It would be of interest to see if this type of treatment, which was well tolerated by mice, would be beneficial in other types of virally induced disease, including AIDS.
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PMID:Curative effect of split low dosage total-body irradiation on murine AIDS induced by Friend virus: the results and the possible mechanism. 874

In this study, we analyze effects of IFN-gamma on the proliferation of normal human mammary epithelial cells (MECs) and several mammary carcinoma cell lines. We demonstrate that IFN-gamma blocks the proliferation of MECs in a time- and concentration-dependent manner. This growth arrest is irreversible and occurs at a specific stage in the G1 phase of the cell cycle. IFN-gamma caused a rapid (within 12-24 h) down-regulation of cyclin A, c-myc, and cdc2 proteins, as well as a disappearance of hyperphosphorylated forms of the retinoblastoma family proteins, Rb and p130. The synthesis of several other growth control proteins, p53, p21/Waf1, and proliferating cell nuclear antigen, was down-regulated between 24 and 48 h. In MECs synchronized by epidermal growth factor deprivation and released for cell cycle traverse by re-addition of epidermal growth factor to the medium, IFN-gamma was able to block DNA synthesis only if added in the first 6 to 7 h after epidermal growth factor. The block in Rb phosphorylation and cyclin A expression was coordinately regulated during the same narrow window of G1. Several mammary carcinoma cell lines demonstrated resistance to the growth-inhibitory effects of IFN-gamma and did not exhibit down-regulation of cdc2 and cyclin A expression or a change in hyperphosphorylation of Rb when treated with IFN-gamma. Initial studies suggest, in some carcinoma cell lines, that resistance to IFN-gamma may be caused by defects in the IFN-gamma signal transduction pathway (measured by expression of the IFN-gamma-responsive gene GBP), while resistance in others may be due to defects in cell cycle regulatory proteins that are the targets of IFN-gamma action.
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PMID:Gamma-interferon induces an irreversible growth arrest in mid-G1 in mammary epithelial cells which correlates with a block in hyperphosphorylation of retinoblastoma. 883 59

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.
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PMID:Cytokine and low-level nitric oxide prestimulation block p53 accumulation and apoptosis of RAW 264.7 macrophages. 895 10

The mechanism by which IFN-gamma induces cell cycle arrest and cell death in primary cultured hepatocytes was examined. The cell death exhibits apoptotic characters such as the appearance of apoptotic bodies and DNA fragmentation. IFN-gamma induced cell cycle arrest at the initial stage, followed by cell death. A protein synthesis inhibitor, cycloheximide, significantly inhibited cell death, implying that IFN-gamma induces de novo proteins involved in the death of hepatocytes. One of the most important apoptosis-related proteins, p53, was induced by IFN-gamma in hepatocytes in a dose- and time-dependent manner. Northern blot analysis demonstrated that IFN-gamma enhanced p53 mRNA expression as well as p21(WAF1/Cip1/Sdi1) mRNA expression, which is mediated by the increased expression of the p53 protein. Interestingly, IFN-gamma also induced cell death in p53-deficient hepatocytes. The cell death occurred rather earlier in p53-deficient cells than in normal hepatocytes. However, the cell death was not accompanied by apoptotic bodies. Therefore, IFN-gamma-induced hepatocyte cell death is p53-independent, and p53 may contribute to the apoptotic characters. In conclusion, IFN-gamma is supposed to cause cell cycle arrest by inducing p53 and p21(WAF1/Cip1/Sdi1), and it was demonstrated that IFN-gamma induces p53-independent cell death in primary cultured hepatocytes.
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PMID:Analysis of IFN-gamma-induced cell cycle arrest and cell death in hepatocytes. 916 17

Interferons (IFNs) induce growth arrest and terminal differentiation through regulation of proliferative genes in a variety of cell types including tumor cells. Growth of melanoma cells is believed to be controlled by the cyclin-dependent kinase inhibitor, mda-6/WAF1/CIP1 gene. IFNs affect the expression of WAF1 in several cell types, including human melanomas. In our earlier reports we demonstrated the antitumor and anticellular activities of different IFN-types on B16 murine melanoma cells. The present study aimed to demonstrate the involvement of mda-6/WAF1 and related cyclin-dependent kinases in antitumor action of different IFN-types in B16 melanoma cells. IFN-alpha has been proven to be a potent inducer of mda-6/WAF1, also inhibiting cyclin-dependent kinases, such as cdc2- and cdk2-kinase. This induction is p53-independent. However, IFN-gamma affects B16 cells differently, it induces p53 activity without inducing WAF1. The combination of IFN-alpha plus IFN-gamma is additive rather than synergistic. Our data demonstrate differential effects of different IFNs on murine B16 melanoma cells which may have relevance in nonsurgical treatment of melanomas.
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PMID:Interferon regulates expression of mda-6/WAF1/CIP1 and cyclin-dependent kinases independently from p53 in B16 murine melanoma cells. 916 13

Interferon (IFN)-gamma increases the sensitivity of tumor cell lines, many of which are p53 mutants, to tumor necrosis factor-alpha-mediated and anti-Fas antibody-mediated cell death. To better understand the mechanism of IFN-gamma action in modulating the cell death response independently of p53 function, we analyzed the death of the human colon adenocarcinoma cell line, HT-29, following treatment with IFN-gamma and various cytotoxic agents. Here we show that IFN-gamma modulates cell death by sensitizing the cells to killing by numerous pro-apoptotic stimuli but not pro-necrotic stimuli. Furthermore, we show that select genes from several important apoptosis-related gene families are induced by IFN-gamma, including the apoptosis-signaling receptors CD95 (Fas/APO-1) and TNFR 1 and interleukin-1beta-converting enzyme (Ice) family members Ice, CPP32 (Yama, apopain), ICErel-II (TX, Ich-2), Mch-3 (ICE-LAP3, CMH-1), Mch-4, and Mch-5 (MACH, FLICE). Of the bcl-2 family members, IFN-gamma directly induced bak but notably not bax, which is activated by p53. The IFN-responsive transcriptional activator interferon regulatory factor-1 was also strongly induced and translocated into the nucleus following IFN-gamma treatment. We propose that IFN-gamma modulates a p53-independent apoptotic pathway by both directly and indirectly inducing select apoptosis-related genes.
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PMID:Interferon-gamma modulates a p53-independent apoptotic pathway and apoptosis-related gene expression. 919 41


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