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)

The chromosomal region 8p21 contains a number of putative tumor suppressor genes and is a frequent site of translocations in head and neck cancers. Recently, a novel tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor gene, KILLER/DR5, a member of the tumor necrosis factor receptor family, was identified as a potential mediator in p53-dependent apoptosis and mapped to 8p21 by fluorescence in situ hybridization. We have determined the genomic structure of KILLER/DR5 and performed sequence analysis of all 10 coding exons in 20 primary head and neck cancers with allelic loss of chromosome 8p. To screen for a subset of mutations localized to the functional cytoplasmic death domain, we sequenced this region in an additional 40 primary head and neck cancers. We found two alterations in this domain, including a 2-bp insertion at a minimal repeat site, introducing a premature stop codon and resulting in a truncated protein. This KILLER/DR5 mutation was also present in the germ line of the affected patient, and the tumor did not have a p53 mutation by sequence analysis. Transfection studies in head and neck squamous cell carcinoma and colon and ovarian carcinoma cell lines revealed loss of growth-suppressive function associated with the tumor-derived KILLER/DR5 truncation mutant. These observations provide the first evidence for mutation of a TRAIL death receptor gene in a human cancer, leading to loss of its apoptotic function.
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PMID:Rare loss-of-function mutation of a death receptor gene in head and neck cancer. 972 51

Despite what is known about the early signaling events in tumor necrosis factor (TNF) alpha-induced apoptosis, characterization of the downstream events remains largely undefined. It is now known that a cross-talk exists between the interferon and TNF-alpha pathways. This linkage allows recruitment of the cell proliferation suppressor PKR (dsRNA-dependent protein kinase) from the interferon pathway to play a pivotal role in TNF-alpha-induced apoptosis. In this study, we took advantage of the differential TNF-alpha susceptibilities of human promonocytic U937 subclones, deficient in or overexpressing PKR, to further characterize the role of PKR in apoptosis. By reverse transcription-polymerase chain reaction, we demonstrated that TNF-alpha transiently induces the tumor suppressor p53 in U937 cells. This p53 induction lags behind the TNF-alpha induction of PKR by 1 h. By cell viability determination, ultrastructural studies, apoptotic DNA laddering, and antisense techniques, it was shown that inhibition of p53 expression in PKR-overexpressing U937 cells abrogates the TNF-alpha-induced apoptosis in these cells. Conversely, overexpressing wild type p53 in PKR-deficient U937 cells confers the susceptibility of these cells to TNF-alpha-induced apoptosis. This latter result indicates that p53 induction is an event downstream of TNF-alpha-induced up-regulation of PKR, thereby further establishing the critical role of p53 in TNF-alpha-induced apoptosis in U937 cells. PKR-overexpressing U937 cells were found to possess a constitutively higher level of p53, which partly explains why these cells spontaneously undergo apoptosis even without TNF-alpha treatment. Finally, a model is presented on the interplay between PKR and p53 in effecting TNF-alpha-induced apoptosis in U937 cells.
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PMID:Tumor suppressor p53 as a component of the tumor necrosis factor-induced, protein kinase PKR-mediated apoptotic pathway in human promonocytic U937 cells. 973 81

Ethanol ingestion may interrupt the proregenerative signal transduction that is initiated by injury-related cytokines such as tumor necrosis factor (TNF)-alpha and TNF-alpha- inducible cytokines including interleukin (IL)-6. To test this theory, liver regeneration, TNF-alpha and IL-6 expression, and cytokine-regulated prereplicative events were compared in ethanol-fed rats and isocalorically fed controls after 70% partial hepatectomy (PH). Ethanol feeding inhibits hepatocyte replication and recovery of liver mass after PH but generally promotes induction of both cytokines in the liver and extrahepatic tissues (i.e., white adipose tissue). Cytokine-regulated events that occur early in the prereplicative period are influenced differentially. TNF-alpha-dependent increases in hepatic nuclear factor-kappaB (NF-kappaB) p50 and p65 expression and DNA binding activity are prevented, whereas IL-6-dependent inductions of hepatic Stat-3 phosphorylation and DNA binding activity occur normally. In contrast, events (e.g., induction of cyclin D1, cdk-1, cyclin D3, and p53 mRNA) that occur at the end of the prereplicative period are uniformly inhibited. These findings indicate that chronic ethanol ingestion arrests the regenerative process during the prereplicative period and demonstrate that increased TNF-alpha, IL-6 and Stat-3 are not sufficient to assure hepatocyte proliferation after PH.
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PMID:Effects of chronic ethanol consumption on cytokine regulation of liver regeneration. 975 99

Protein kinase Cdelta (PKCdelta) is proteolytically cleaved and activated at the onset of apoptosis induced by DNA-damaging agents, tumor necrosis factor, and anti-Fas antibody. A role for PKCdelta in apoptosis is supported by the finding that overexpression of the catalytic fragment of PKCdelta (PKCdelta CF) in cells is associated with the appearance of certain characteristics of apoptosis. However, the functional relationship between PKCdelta cleavage and induction of apoptosis is unknown. The present studies demonstrate that PKCdelta associates constitutively with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs). The results show that PKCdelta CF phosphorylates DNA-PKcs in vitro. Interaction of DNA-PKcs with PKCdelta CF inhibits the function of DNA-PKcs to form complexes with DNA and to phosphorylate its downstream target, p53. The results also demonstrate that cells deficient in DNA-PK are resistant to apoptosis induced by overexpressing PKCdelta CF. These findings support the hypothesis that functional interactions between PKCdelta and DNA-PK contribute to DNA damage-induced apoptosis.
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PMID:Inactivation of DNA-dependent protein kinase by protein kinase Cdelta: implications for apoptosis. 977 85

Human acinic cell adenocarcinoma cell (HACC) line was established from the pleural effusion that contains metastatic tumor cells of acinic cell adenocarcinoma of papillary and microcystic type originating from the parotid gland. The HACC cells grew in an adherent monolayer with a doubling time of 66 h. Implanted tumor of SCID mice revealed similar histological findings to that of the primary tumor. The HACC cells produced mucin and expressed epithelial markers as well as alpha1-antitrypsin and lysozyme, whereas salivary peptide P-C was expressed in cultured HACC cells but not in the primary and implanted HACC cell tumors. S-100 protein was also expressed in both the primary tumor and HACC cell line. Neither amplification of common oncogenes nor expression of p53 was observed. The receptor for epidermal growth factor (EGF) was expressed, indicating EGF and transforming growth factor-alpha (TGF-alpha) enhanced the growth of the HACC line. Unexpectedly, tumor necrosis factor-a (TNF-alpha) also enhanced the growth of the HACC line significantly. However, there was no evidence of autocrine growth using these growth factors. In contrast, TGF-beta1 inhibited the growth of the HACC cell line through apoptosis. The HACC cell line has features similar to both acinar and intercalated ductal cells of the salivary gland. Epidermal growth factor, TGF-alpha and TNF-alpha are potential growth factors for the HACC cell line. The HACC cell line may be a good model for studying the biological behavior of salivary gland neoplasms.
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PMID:Characterization of a newly established human acinic cell adenocarcinoma cell line (HACC) originating from the salivary gland: morphological features and role of various growth factors on the growth of the HACC cell line. 978 63

Nitric oxide (NO) is thought to play an important role in neurotransmission, inflammation, and regulation of cell death in the mammalian brain. Here, we examined the synthesis and biological effects of NO in human malignant glioma cells. Exposure to cytokines such as interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha or interleukin (IL)-1beta and lipopolysaccharide (LPS) induced NO synthesis in rat C6 and A172 human glioma cells, but not in LN-229, T98G or LN-18 human malignant glioma cells. Induced release of NO involved enhanced expression of inducible NO synthase (iNOS). Failure to detect NO release in the latter cell lines was not overcome by neutralization of endogenous TGF-beta or by coexposure to cytokines, LPS, and antioxidants. Apoptosis induced by CD95 ligand (CD95L) did not involve NO formation. Neither NOS inhibitors nor NO donators modulated CD95L-induced apoptosis. Dexamethasone (DEX)-mediated protection of glioma cells from CD95L-induced apoptosis was also independent of DEX effects on NO metabolism. DEX inhibited not only cytokine/LPS-evoked NO release but also attenuated the toxicity of NO in three of five cell lines. Forced expression of temperature-sensitive p53 val135 in C6 cells in either mutant or wild-type conformation inhibited cytokine/LPS-induced NO synthesis. Further, accumulation of p53 in both mutant or wild-type conformation protected glioma cells from the toxicity of exogenous NO, consistent with a gain of p53 function associated with p53 accumulation. We conclude that resistance to NO-dependent immune defense mechanisms may contribute to the malignant progression of human cancers with p53 alterations, notably those associated with the accumulation of mutant p53 protein.
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PMID:Synthesis and biological effects of NO in malignant glioma cells: modulation by cytokines including CD95L and TGF-beta, dexamethasone, and p53 gene transfer. 981 63

The introduction of adenovirus 5 E1A into the SKOV3ip1 ovarian cancer cell line was shown previously to suppress HER2/neu expression and reduce the malignant potential of these cells (Yu et al., Cancer Res., 53: 891-898, 1993). In this report, we show that reduction of p185 in cells stably expressing E1A protein was coincident with increased sensitivity to cytotoxic agents. The LD50 of cisplatin was reduced 6-fold, and the LD50 of paclitaxel and doxorubicin was reduced 10-fold in E1A-expressing cells compared with control cells. The growth of SKOV3ip1 and control cells was unchanged in the presence of 150 ng/ml of tumor necrosis factor-alpha, whereas the growth of E1A-expressing cells was reduced by 30 to 40%. When we used a physiologically obtainable concentration of paclitaxel (0.5 microM), DNA laddering consistent with apoptotic cell death was seen after a 24-h exposure in the E1A-expressing cells, whereas laddering and DNA fragmentation were only detected in DNA from control cells after longer exposure (48 h) at a 20-fold higher concentration of paclitaxel. The SKOV3ip1 cells do not express p53 protein; hence, the induction of apoptosis by paclitaxel is through a p53-independent pathway. Despite their diverse mechanisms of action, the cytotoxic effects of cisplatin, doxorubicin, paclitaxel, and tumor necrosis factor-alpha were enhanced by the expression of E1A proteins in the SKOV3ip1 ovarian cancer cells. This suggests that these agents share a common final pathway of cell killing, which may represent a potential therapeutic target in resistant ovarian cancers.
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PMID:Adenovirus E1A expression enhances the sensitivity of an ovarian cancer cell line to multiple cytotoxic agents through an apoptotic mechanism. 981 92

Expression of the 243-residue form of the adenovirus E1A protein in the absence of other viral proteins triggers apoptosis by a pathway that requires p53. This pathway includes processing and activation of initiator procaspase-8, redistribution of cytochrome c, and activation of procaspase-3. Bcl-2 functions at or upstream of procaspase-8 processing to inhibit all of these events and prevent cell death. This contrasts with the anti-apoptotic influence of Bcl-2 family proteins in the cell death pathway induced by Fas ligand or tumor necrosis factor (TNF), in which Bcl-2 typically acts downstream of Fas/TNFR1-mediated activation of caspase-8. Moreover, E1A induces procaspase-8 processing and cell death in cells deleted of FADD, an adaptor protein critical for Fas/TNFR1 activation of caspase-8. The results indicate that E1A is capable of activating caspase-8 by a Bcl-2-inhibitable pathway that does not involve autocrine stimulation of FADD-dependent death receptor pathways.
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PMID:E1A-induced processing of procaspase-8 can occur independently of FADD and is inhibited by Bcl-2. 983 71

Degradation of extracellular matrix by hyaluronidase increases murine L929 cell sensitivity to tumor necrosis factor (TNF) cytotoxicity. Seeding and culturing L929 cells onto the matrix of serum fetuin and the hyaluronate-binding inter-alpha-inhibitor resulted in inhibition of hyaluronidase-enhanced TNF killing, suggesting that the release of these proteins from hyaluronidase-degraded matrix confers cellular TNF susceptibility. Metabolic labeling studies showed that hyaluronidase mediated de novo protein synthesis and down regulated several proteins in L929 cells. Specifically, hyaluronidase upregulated p53 protein expression (>200%) but down regulated a p85 inter-alpha-inhibitor-like protein (>90%) in L929 cells, whereas it had no effect on the protein levels of ICH-1, Bcl-xL, Bcl-2, Fas ligand, CAS (cellular apoptosis susceptible protein), TIAR (an RNA-binding protein) and alpha-tubulin. Conceivably, hyaluronidase enhancement of TNF sensitivity in L929 cells is p53-dependent and the matrix inter-alpha-inhibitor contributes a protective role against TNF cytotoxicity.
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PMID:p53 overexpression and downregulation of inter-alpha-inhibitor are associated with hyaluronidase enhancement of TNF cytotoxicity in L929 fibroblasts. 983 19

Apoptosis is considered to be a protective mechanism that limits lung injury. However, apoptosis might contribute to the inflammatory burden present in the injured lung. The exposure of mice to bleomycin (BLM) is a well-established model for the study of lung injury. BLM exposure induces DNA damage and enhances tumor necrosis factor (TNF)-alpha expression in the lung. To evaluate the importance of alveolar macrophage (AM) apoptosis in the pathogenesis of lung injury, we exposed BLM-sensitive (C57BL/6) and BLM-resistant (BALB/c) mice to BLM (120 mg/kg) and studied the induction of apoptosis [by light-microscopy changes (2, 8, 12, 24, 48, and 72 h) and annexin V uptake by flow cytometry (24 h)], the secretion of TNF-alpha (measured by ELISA), and the expression of p53 (by immunoblotting) in AM retrieved from these mice. BLM, but not vehicle, induced apoptosis in AM from both murine strains. The numbers of apoptotic AM were significantly greater (P < 0.001) in C57BL/6 mice (52.9%) compared with BALB/c mice (40.8%) as demonstrated by annexin V uptake. BLM induction of apoptosis in AM was preceded by an increased secretion of TNF-alpha in C57BL/6 but not in BALB/c mice. Furthermore, double TNF-alpha receptor-deficient mice, developed on a C57BL/6 background, demonstrated significantly (P < 0.001) lower numbers of apoptotic AM compared with C57BL/6 and BALB/c mice. BLM also enhanced p53 expression in AM from both murine strains. However, p53-deficient mice developed BLM-induced lung injury, exhibited similar lung cell proliferation (measured as proliferating cell nuclear antigen immunostaining), and accumulated similar amounts of lung hydroxyproline (65 +/- 6.9 microgram/lung) as did C57BL/6 (62 +/- 6.5 microgram/lung) mice. Therefore, AM apoptosis is occurring during BLM-induced lung injury in a manner that correlates with murine strain sensitivity to BLM. Furthermore, TNF-alpha secretion rather than p53 expression contributes to the difference in murine strain response to BLM.tumor necrosis factor; strain susceptibility
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PMID:Alveolar macrophage apoptosis and TNF-alpha, but not p53, expression correlate with murine response to bleomycin. 984 59


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