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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis B virus produces chronic infections of the liver leading to cirrhosis and hepatocellular carcinoma. The X protein of hepatitis B virus (HBx) is a multifunctional protein that can interact with p53 but can also influence a variety of signal transduction pathways within the cell. In most instances this small viral protein favors cell survival and probably initiates hepatocarcinogenesis. HBx upregulates the activity of a number of transcription factors including NF-kappa B, AP-1, CREB, and TBP. However, the majority of HBx is localized to the cytoplasm where it interacts with and stimulates protein kinases such as protein kinase C, Janus kinase/STAT, IKK, PI-3-K, stress-activated protein kinase/Jun N-terminal kinase, and protein kinase B/Akt. This small viral protein can localize to the mitochondrion. HBx may act as an adaptor or kinase activator to influence signal transduction pathways. This review will attempt to analyze the involvement of HBx in signal transduction pathways during hepatitis B viral infections and hepatocellular carcinoma development.
Cytokine Growth Factor Rev
PMID:X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis. 1132 2

Exposure of hematopoietic cells to DNA-damaging agents induces p53-independent cell cycle arrest at a G(1) checkpoint. Previously, we have shown that this growth arrest can be overridden by cytokine growth factors, such as erythropoietin or interleukin-3, through activation of a phosphatidylinositol 3-kinase (PI 3-kinase)/Akt-dependent signaling pathway. Here, we show that gamma-irradiated murine myeloid 32D cells arrest in G(1) with active cyclin D-cyclin-dependent kinase 4 (Cdk4) but with inactive cyclin E-Cdk2 kinases. The arrest was associated with elevated levels of the Cdk inhibitors p21(Cip1) and p27(Kip1), yet neither was associated with Cdk2. Instead, irradiation-induced inhibition of cyclin E-Cdk2 correlated with absence of the activating threonine-160 phosphorylation on Cdk2. Cytokine treatment of irradiated cells induced Cdk2 phosphorylation and activation, and cells entered into S phase despite sustained high-level expression of p21 and p27. Notably, the PI 3-kinase inhibitor, LY294002, completely blocked cytokine-induced Cdk2 activation and cell growth in irradiated 32D cells but not in nonirradiated cells. Together, these findings demonstrate a novel mechanism underlying the DNA damage-induced G(1) arrest of hematopoietic cells, that is, inhibition of Cdk2 phosphorylation and activation. These observations link PI 3-kinase signaling pathways with the regulation of Cdk2 activity.
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PMID:Dna damage-induced G(1) arrest in hematopoietic cells is overridden following phosphatidylinositol 3-kinase-dependent activation of cyclin-dependent kinase 2. 1150 54

Cytokine oncostatin M (OM) exerts growth-inhibitory and differentiative effects on breast cancer cells. Previously we showed that the transcription from the p53 gene in breast cancer cells was down regulated by OM. To elucidate the molecular mechanisms underlying the OM effect on p53 transcription, in this study, we dissected the p53 promoter region and analysed the p53 promoter activity in breast tumor cells. We showed that treatment of MCF-7 cells with OM induced a dose- and time-dependent suppression of p53 promoter activity. The p53 promoter activity was decreased to 35% of control at 24 h and further decreased to 20% at 48 h by OM at concentrations of 5 ng/ml and higher. Deletion of the 5'-flanking region of the p53 promoter from -426 to -97 did not affect the OM effect. However, further deletion to -40 completely abolished the repressive effect of OM. The p53 promoter region -96 to -41 contains NF-kappaB and c-myc binding sites, and a newly identified UV-inducible element PE21. Mutations to disrupt NF-kappaB binding or c-myc binding to the p53 promoter decreased the basal promoter activity without affecting the OM-mediated suppression, whereas mutation at the PE21 motif totally abolished the OM effect. We further demonstrated that insertion of PE21 element upstream of the thymidine kinase minimal promoter generated an OM response analogous to that of the p53 promoter. Finally, we detected the specific binding of a nuclear protein with a molecular mass of 87 kDa to the PE21 motif. Taken together, we demonstrate that OM inhibits the transcription of the p53 gene through the PE21 element. Thus, the PE21 element is functionally involved in p53 transcription regulated by UV-induction and OM suppression.
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PMID:The critical role of the PE21 element in oncostatin M-mediated transcriptional repression of the p53 tumor suppressor gene in breast cancer cells. 1178 35

Antigen-presenting cells (APCs) are crucial for the generation of a functional immune response to pathogens. Furthermore, there is abundant evidence for their importance in primary T-cell activation, B-cell maturation and maintenance of an ongoing immune response. In the present study, we have analysed phenotypic characteristics and functionality of a p53-deficient APC cell line (JawsII) derived from mouse bone marrow culture. We show that unstimulated JawsII cells express low surface levels of major histocompatibility complex (MHC) and costimulatory molecules, both of which can be upregulated upon treatment with cytokines in vitro. Cytokine stimulation also leads to an enhanced T-cell activation capacity but has only little effect on cytokine release by the JawsII cells themselves. On the contrary, stimulation of the JawsII cells with lipopolysaccharide (LPS) leads to the production and secretion of high amounts of interleukin-1 (IL-1), IL-6 and tumour necrosis factor-alpha (TNF-alpha) but no increase in the surface levels of MHC and costimulatory molecules, and has only little effect on the T-cell activation capacity. Our data suggest that the effects observed upon treatment with cytokines or LPSs are complementary, and that both stimuli are needed for mediating a strong and efficient JawsII cell-dependent T-cell activation.
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PMID:Treatment of an immortalized APC cell line with both cytokines and LPS ensures effective T-cell activation in vitro. 1241 Jul 99

Biologic therapy of ovarian cancer has been conducted using nonspecific biologic response modifiers, cytokines, monoclonal antibodies (MAbs), vaccines, and gene therapy. Antibodies directed toward her2/neu have also been studied. Phase I and II gene therapy trials using adenoviral vectors containing a wild-type or modified p53 have shown that the treatment is well tolerated. Phase II and III trials are ongoing with MAbs directed against CA-125 (MAb B43.13) and an antibody directed against HMFG1 (anti-HMFG1-yttrium-90-labeled antibody). The trials have shown that these agents are well tolerated and that immunologic responses occur, although the ultimate clinical value of these agents remains to be determined. Prolonged survival after MAb B43.13 treatment has been correlated with changes in several immune parameters, including human antimurine antibody, Ab2, anti-CA-125 antibody development, and induced T-cell immunity. Clinical trials using a MAb directed toward the encoded products of her2/neu have shown minimal activity against ovarian cancer in a phase I and II trial conducted by the Gynecologic Oncology Group. Cytokine therapies have been administered systemically and intraperitoneally. Intracavitary interferon alfa, interferon gamma, and interleukin-2 alone or in combination with cytotoxic therapy in phase I and II trials demonstrated intraperitoneal lymphoid cell stimulation and produced antitumor responses. A randomized trial of chemotherapy with or without interferon gamma in primary treatment produced a response and a progression-free survival advantage in the arm that incorporated the interferon gamma, without a statistically significant benefit in overall survival. A phase III study of interferon gamma in combination with first-line chemotherapy is currently ongoing.
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PMID:Biologic and immunologic therapies for ovarian cancer. 1274 31

Various human colon cancer cell lines tested in vitro differed significantly in susceptibility to growth inhibition of recombinant human interferon-beta (rHuIFN-beta). Two p53-mutant lines, COH and CC-M2, derived from high-grade colon adenocarcinoma, showed signs of apoptosis after treatment with 250 IU/ml of HuIFN- beta in the culture medium. The similarly p53-mutated HT-29 line from a grade I adenocarcinoma showed no apoptosis, however, and only cell cycle G1/G0 or S phase retardation with 1000 IU/ml HuIFN-beta. After HuIFN-beta exposure, COH and CC-M2 cells showed increased levels of Fas and FasL proteins, alteration of mitochondrial membrane potential, and activation of caspase-9, caspase-8, and caspase-3 in a time-dependent manner. Treatment of COH and CC-M2 cells with anti-FasL antibodies or rFas/Fc fusion protein, however, could not prevent the apoptosis induced by HuIFN-beta. In contrast, cell-permeable specific inhibitors of the three caspases could inhibit the DNA fragmentation and cell death but not the mitochondrial membrane potential changes. Treatment with mitochondria-stabilizing reagents could significantly abrogate the apoptosis and caspase activation induced by HuIFN-beta. These results suggest that in COH and CC-M2 colon cancer cell lines, HuIFN-beta induces apoptosis mainly through mitochondrial membrane alteration and subsequent activation of the caspase cascade pathway, but not by the Fas/FasL interaction or the p53-dependent apoptotic mechanism.
J Interferon Cytokine Res 2004 Apr
PMID:IFN-beta induces caspase-mediated apoptosis by disrupting mitochondria in human advanced stage colon cancer cell lines. 1514 69

Interferon (IFN)-stimulated gene (15 kDa) (ISG15) is a ubiquitin-like protein that forms covalent conjugates with cellular proteins. ISG15 is induced by IFN, microbial challenge, and p53, suggesting that it represents a genetic response that is shared among diverse stress stimuli. To investigate the regulation of this posttranslational modification pathway by a genotoxic chemotherapeutic agent, we examined ISG15 induction and conjugation in cells treated with the topoisomerase I (topoI) poison, camptothecin (CPT). CPT induced ISG15mRNA, and induction required protein synthesis and a functional p53 protein. However, IFN and the Jak-Stat components of the IFN signaling pathway were dispensable for CPT induction of ISG15. CPT induced free ISG15 and conjugates in a dose-dependent and time-dependent manner. A single 55-kDa protein was the prominent CPT-induced ISG15 conjugate and localized to the nuclear compartment. CPT-induced ISG15 conjugates were distinct from those induced by IFN; however, CPT treatment dramatically enhanced ISG15 conjugation in response to IFN. These findings provide the first evidence of a stimulus-specific induction of discrete ISG15 conjugate species and demonstrate that treatment with a combination of cancer therapeutic agents can cooperate to enhance ISG15 conjugation. Identification of the specific ISG15 conjugates induced by chemotherapeutic agents may reveal novel molecular targets.
J Interferon Cytokine Res 2004 Nov
PMID:Camptothecin induces the ubiquitin-like protein, ISG15, and enhances ISG15 conjugation in response to interferon. 1568 17

PL74, a novel member of the TGFbeta superfamily that has highest expression in placenta, is a multifunctional peptide that can induce differentiation, inhibit inflammatory stimulation of TNFalpha, and execute apoptosis after p53 overexpression and cytotoxic injury. To study its expression and function in placenta and preeclampsia, we first determined mRNA expression in nine normal and 10 preeclamptic placentas. PL74 mRNA was overexpressed by 57.3% in preeclampsia. Transfection of PL74 into term cytotrophoblasts resulted in increased apoptosis by terminal uridine deoxynucleotidyl nick end labeling labeling (control, 2.8 +/- 0.5%; PL74, 19.1 +/- 0.2%; P < 0.005). Addition of PL74 protein to HTR8/SVneo extravillous cytotrophoblast cells showed a dose-response (0-100 ng/ml) inhibition of [3H]thymidine uptake and increase in apoptosis shown by terminal uridine deoxynucleotidyl nick end labeling and histone-associated DNA fragment ELISA (control, 0.11 +/- 0.01 absorbance units; PL74, 0.21 +/- 0.01; P < 0.01). PL74 did not alter cytotrophoblast invasion using a Matrigel in vitro invasion assay. Cytokine regulation of PL74 mRNA expression in term cytotrophoblasts showed that epidermal growth factor and IFNgamma increased PL74 expression, but TGFbeta and TNFalpha had no effect. Transfection of antisense PL74 into term cytotrophoblast cells resulted in an inhibition of spontaneous differentiation at 2 and 24 h of culture (control vector, 30.8 +/- 3.1% and 26.4 +/- 1.2%; antisense PL74, 17.6 +/- 1.8%and 12.6 +/- 1.4% syncytial units, at 2 and 24 h respectively; P < 0.01). We conclude that PL74 is overexpressed in preeclampsia and may thus promote apoptosis of cytotrophoblasts at the expense of differentiation. PL74 secretion is induced by IFNgamma and may play a role in abnormal placental responses in preeclampsia.
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PMID:PL74, a novel member of the transforming growth factor-beta superfamily, is overexpressed in preeclampsia and causes apoptosis in trophoblast cells. 1570 26

Interferon alpha (IFN-alpha) is an approved treatment in metastatic renal cell carcinoma (RCC). The underlying mechanisms are far from being clear, but are presumed to be a combination of stimulation of cell-mediated cytotoxicity, direct antiproliferative activity and antiangiogenic effects. Recently, the role of p53 in the cellular response to IFN-alpha has been proposed in other tumor models (hepatoblastoma). We therefore studied the expression of p53 during IFN-alpha treatment using two freshly established RCC cell lines RCC5 and RCC7. While IFN-alpha treatment significantly enhanced the expression of p53 in RCC7, no changes were observed in RCC5. Cell viability under IFN-alpha remained unchanged in both cell lines. Following gamma-irradiation, a p53-activating stimulus, an enhanced cell death was observed in IFN-alpha-treated RCC7 but not in RCC5. We further demonstrate that there were no changes in Bcl-2- and Bax-expression, two target genes regulated by p53. However, intracellular staining revealed that cell death induced by IFN-alpha and gamma-irradiation was preceded by a shift of Bax to the mitochondria in RCC7. Our results suggest a role of p53 and its downstream target Bax, in the control of RCC sensitivity to IFN-alpha.
Eur Cytokine Netw 2005 Jun
PMID:The sensitivity of renal cell carcinoma cells to interferon alpha correlates with p53-induction and involves Bax. 1594 83

DNA hypermethylation in gene promoters is an epigenetic mechanism regulating gene expression in cellular immortalization, an important step in carcinogenesis. Previously, we studied the genes dysregulated during immortalization using spontaneously immortalized fibroblasts from patients with Li-Fraumeni syndrome (LFS), who carry a germline mutation in the tumor suppressor gene p53. We found that multiple interferon (IFN) signaling pathway genes were regulated by epigenetic silencing. In this study we focused on a key regulator of that pathway, the signal transducer and transcription activator 1 (Stat1) gene. Although Stat1 is downregulated after cellular immortalization and upregulated in immortal MDAH041 cells after 5-aza-2'-deoxycytidine (5-aza-dC) treatment, we detected no methylation of the Stat1 promoter region in these cells before or after immortalization. To analyze the function of Stat1 in immortalization, we expressed Stat1 in immortal MDAH041 cells by stable infection, expecting to induce IFN-regulated genes or cellular senescence or both. However, the overexpression of Stat1 alone was not sufficient to repress the proliferation rate of immortal MDAH041 cells or induce senescence in immortal MDAH041 cells. We concluded that factor(s) additional to Stat1 (whether IFN dependent or not) are required for the immortalization of LFS fibroblasts.
J Interferon Cytokine Res 2006 Jan
PMID:Stat1 expression is not sufficient to regulate the interferon signaling pathway in cellular immortalization. 1642 44


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