Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001486 (Adenovirus)
 3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hygromycin B, an aminoglycoside antibiotic that is widely used to establish stable mammalian cell lines that carry a bacterial gene conferring resistance to the drug, is shown here to induce apoptotic programmed cell death in susceptible cells. Dying cells exhibited typical features of apoptosis, including cell shrinkage, membrane blebbing, nuclear pyknosis, and extensive internucleosomal fragmentation of DNA. Employing concentrations of hygromycin B that are typically used for selecting stable cell lines, we show that susceptible cells die rapidly, exhibiting the morphological properties of apoptosis by 18 h and detectable DNA fragmentation as early as 2 h after receiving the drug. G418, on the other hand, required days to cause cell death, which was not accompanied by internucleosomal DNA fragmentation. Apoptotic cell killing by hygromycin B did not require expression of wild-type p53 and was suppressed by both Bcl-2 and the Adenovirus type 5 E1B 19-kDa protein.
 ...
PMID:Induction of p53-independent apoptosis by hygromycin B: suppression by Bcl-2 and adenovirus E1B 19-kDa protein. 758 55

Adenovirus E1B 19K protein prevents premature death of adenovirus-infected cells. Viral mutants (19K mutants) defective in the 19K protein induce enhanced cell death, resulting in fragmentation of viral and cellular DNA. The 19K protein can also suppress the effects of certain external cell death-inducing stimuli, such as tumor necrosis factor alpha and various DNA-damaging agents that induce apoptosis. We have examined viral infection of permissive human cells and nonpermissive rat cells to determine if the 19K mutant induces apoptotic or necrotic type of cell death. Infection of normal rat kidney cells with an adenovirus type 2 19K deletion mutant induces internucleosomal DNA fragmentation and condensation of nuclear chromatin. Electron microscopic examination of these cells revealed the presence of condensed subnuclear bodies characteristic of apoptosis. In contrast, infection of human A549 cells induces random DNA fragmentation, and these cells do not exhibit characteristic condensation of the nuclear chromatin but contain enlarged nuclei loaded with virus particles. Therefore, it appears that adenovirus infection induces both apoptotic and necrotic types of cell death, depending on the cell type. Both types of cell death can be suppressed by E1B 19K protein. Similarly, a recombinant adenovirus expressing the human Bcl-2 protein but lacking the E1B proteins can efficiently suppress both apoptotic and necrotic cell death induced by adenovirus infection. The requirement of p53 tumor suppressor protein in adenovirus-induced cell death was investigated by infection of human Saos2 and mouse p53 nullizygous (p53-/-) cells lacking p53 tumor suppressor protein.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:p53-independent apoptotic and necrotic cell deaths induced by adenovirus infection: suppression by E1B 19K and Bcl-2 proteins. 775 71

Adenovirus E1B 19 kDa protein protects against cell death induced by viral infection and certain external stimuli. The Bcl-2 protein can functionally substitute for the E1B 19 kDa protein. To identify cellular targets for the 19 kDa protein, we used the two-hybrid screen in yeast. We have isolated cDNAs for three different proteins, designated Nip1, Nip2, and Nip3, that interact with the 19 kDa protein. Mutational analysis indicates that these proteins do not associate with 19 kDa mutants defective in suppression of cell death, suggesting a correlation between interaction of these proteins and suppression of cell death. These proteins also associate with discrete sequence motifs in the Bcl-2 protein that are homologous to motifs of the 19 kDa protein. Our results suggest that two diverse proteins, the E1B 19 kDa and the Bcl-2 proteins, promote cell survival through interaction with a common set of cellular proteins.
 ...
PMID:Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins. 800 Nov 38

Adenovirus E1A expression recruits primary rodent cells into proliferation but fails to transform them because of the induction of programmed cell death (apoptosis). The adenovirus E1B 19,000-molecular-weight protein (19K protein), the E1B 55K protein, and the human Bcl-2 protein each cause high-frequency transformation when coexpressed with E1A by inhibiting apoptosis. Thus, transformation of primary rodent cells by E1A requires deregulation of cell growth to be coupled to suppression of apoptosis. The product of the p53 tumor suppressor gene induces apoptosis in transformed cells and is required for induction of apoptosis by E1A. The ability of Bcl-2 to suppress apoptosis induced by E1A suggested that Bcl-2 may function by inhibition of p53. Rodent cells transformed with E1A plus the p53(Val-135) temperature-sensitive mutant are transformed at the restrictive temperature and undergo rapid and complete apoptosis at the permissive temperature when p53 adopts the wild-type conformation. Human Bcl-2 expression completely prevented p53-mediated apoptosis at the permissive temperature and caused cells to remain in a predominantly growth-arrested state. Growth arrest was leaky, occurred at multiple points in the cell cycle, and was reversible. Bcl-2 did not affect the ability of p53 to localize to the nucleus, nor were the levels of the p53 protein altered. Thus, Bcl-2 diverts the activity of p53 from induction of apoptosis to induction of growth arrest, and it is thereby identified as a modifier of p53 function. The ability of Bcl-2 to bypass induction of apoptosis by p53 may contribute to its oncogenic and antiapoptotic activity.
 ...
PMID:Bcl-2 blocks p53-dependent apoptosis. 813 58

The early transcribed adenovirus proteins E1A and E1B display a variety of functions in the transformation of primary rodent cells and the regulation of apoptosis and transcription. We have recently shown recently that the E1B 19 kDa protein from Adenovirus 5 (Ad 5) can functionally antagonize the stimulatory effect of E1A 13S on the human transcription factor NF-kappaB. Here we show that expression of E1B 19 kDa negatively interfered with the activation of NF-kappaB by different stimuli, such as the E1A 13S protein, and treatment with phorbol ester and tumor necrosis factor alpha. This suggests that E1B 19 kDa acts on a common upstream signaling event. Band shift experiments showed that expression of E1B 19 kDa impaired the generation of the nuclear, DNA-binding form of NF-kappaB. Domain mapping experiments employing various E1B 19 kDa mutants revealed the necessity of a hydrophobic Bcl-2 homology region between amino acids 90 and 96 for NF-kappaB inhibition. Co-transfection experiments showed that the inhibitory effect of E1B 19 kDa on E1A 13S-activated NF-kappaB transcription was gradually lost in the course of time. Thus the continuous stimulatory action of E1A 13S can finally override the antagonistic effects of E1B 19 kDa on NF-kappaB activity. In contrast to E1B 19 kDa, expression of the E1B 55 kDa protein did not result in a de novo activation of NF-kappaB, but co-stimulated the transcriptional potential of activated NF-kappaB.
 ...
PMID:A hydrophobic region within the adenovirus E1B 19 kDa protein is necessary for the transient inhibition of NF-kappaB activated by different stimuli. 870 75

Adenovirus type 2 E1A gene product induces nuclear degeneration and apoptosis of human epithermoid carcinoma cell line MA1 within 72 h after its expression. Western-blot analysis revealed that the level of topoisomerase II alpha begins to decrease posttranscriptionally within 36 h after E1A expression, preceding the onset of DNA fragmentation. The decrease of topoisomerase II alpha was suppressed in the MA1 derivative E1B19k or Bcl-2 expressing cell lines that refractory to E1A-induced apoptosis. Topoisomerase II alpha of the nuclear matrix or prepared by immunoprecipitation was degraded more efficiently in the S10 extract prepared from MA1 cells treated with DEX for 42 h than in the extract from untreated MA1 cells in an ATP and ubiquitin dependent manner. These data suggest that degradation of topoisomerase II alpha is a key event that destines cells to apoptosis, and is catalyzed by the ubiquitin proteolysis pathway that is activated during the latent phase of E1A-induced apoptosis.
 ...
PMID:[Degradation of topoisomerase II alpha precedes nuclei degeneration during adenovirus E1A-induced apoptosis and is mediated by the activation of the ubiquitin dependent proteolysis system]. 874 74

Adenovirus E1B 19-kDa protein (19K) is a member of the Bcl-2 family of suppressors of apoptosis. The suppressors function through heterodimerization with the death promoters, Bax and related proteins, thus establishing a set point within the cell that determines whether or not apoptosis is executed in response to a death signal. Sequence similarities between 19K and Bcl-2 are largely restricted to short Bcl-2 homology (BH) domains that mediate interaction with Bax. The BH1 sequence in 19K is degenerate but nevertheless contains a conserved glycine residue found in all family members that when mutated to alanine in Bcl-2 results in loss of Bcl-2 function and ability to dimerize with Bax (Yin, X.-M., Oltvai, Z. N., and Korsmeyer, S. J. (1994) Nature 369, 321-323). Here, we show that the analogous mutation in BH1 of 19K also abrogates the anti-apoptotic properties of 19K and its ability to interact with Bax, thus establishing the critical importance of this residue within BH1 and the likely similarity of Bcl-2 and 19K function. In distinct contrast to Bcl-2, however, 19K interaction was not detected with Bad, a Bcl-2/Bcl-XL dimerizing protein that can potentially regulate a Bax middle dotBcl-2/Bcl-XL survival set point and reinstate susceptibility to a death signal. Furthermore, the anti-apoptotic function of 19K was not overcome by enforced expression of Bad in transfected cells. This feature of 19K may provide adenovirus with a selective advantage in evading premature induction of apoptosis by the host cell.
 ...
PMID:Adenovirus E1B 19-kDa death suppressor protein interacts with Bax but not with Bad. 879 65

We established a human malignant fibrous histiocytoma (MFH) cell line, MFH-ToE, from a tumor originally developed in the right thigh of a 78-year-old woman. The original tumor histologically consisted of histiocytic, fibroblastic and giant cells. The tumor cells showed immunoreactivity for vimentin and alpha-1-antichymotrypsin, and were positive for acid phosphatase and non-specific esterase, being compatible with MFH. Although the histology of the heterotransplanted tumor into nude mice was similar to that of the primary MFH, the population of giant cells gradually decreased along with the culture passages. Cytogenetic analysis revealed a highly aneuploid nature with varying numbers of chromosomes from 71 to 140. Chromosome 17 showed monosomy and exon 6 to 8 of p53 gene was not amplified by PCR, implying absence of p53 function. Adenovirus vector-mediated wild-type p53 gene was successfully transfected into the MFH-ToE, which showed up-regulation of P53 and P21, as well as gradual up-regulation of Bcl-2 protein. The transfection resulted in cell cycle arrest, but not apoptosis of the MFH-ToE cells. These results revealed unique properties of the MFH-ToE, which might be useful in further studies analyzing pathological and biological characteristics of MFH.
 ...
PMID:Wild-type p53 gene transfer resulted in cell cycle arrest, but not apoptosis of newly established human malignant fibrous histiocytoma cell line. 1053 76

Emerging data indicate that growth factors such as insulin-like growth factor-1 (IGF-1) prevent neuronal death due to nitric oxide (NO) toxicity. On the other hand, growth factors can promote cell survival by acting on phosphatidylinositol 3-kinase (PI3-kinase) and its downstream target, serine-threonine kinase Akt, in various types of cells. Here, we examined the mechanism by which IGF-1 inhibits neuronal apoptosis induced by NO in primary hippocampal neurons. IGF-1 was capable of preventing apoptosis and caspase-3-like activation induced by a NO donor, sodium nitroprusside or 3-morpholin-osydnonimine. Incubation of neurons with a P13-kinase inhibitor, wortmannin or LY294002, blocked the effects of IGF-1 on NO-induced neurotoxicity and caspase-3-like activation. In addition, the P13-kinase inhibitors blocked the effect of IGF-1 on down-regulation in Bcl-2 and upregulation in Bax expression induced by NO. Adenovirus-mediated overexpression of the activated form of Akt significantly inhibited NO-induced cell death, caspase-3-like activation, and changes in Bcl-2 and Bax expression. Moreover, expression of the kinase-defective form of Akt almost completely blocked the effects of IGF-1. These findings suggest that activation of Akt is necessary and sufficient for the effect of IGF-1 and is capable of preventing NO-induced apoptosis by modulating the NO-induced changes in Bcl-2 and Bax expression.
 ...
PMID:Activation of Akt kinase inhibits apoptosis and changes in Bcl-2 and Bax expression induced by nitric oxide in primary hippocampal neurons. 1053 63

Calcineurin is a Ca(2+)/calmodulin-dependent protein phosphatase that is abundantly expressed in several specific areas of the brain, which are exceptionally vulnerable to stroke, epilepsy, and neurodegenerative diseases. In this study, we assessed the effects of high level activity of calcineurin on neuronal cells. Virus-mediated high level constitutive activity of calcineurin rendered neuronal cells susceptible to apoptosis induced by serum reduction or by a brief exposure to calcium ionophore. Adenovirus-mediated, high level forced activity of calcineurin induced cytochrome c/caspase-3-dependent apoptosis in neurons. Preincubation with the calcineurin inhibitors cyclosporin A and FK506 reduced susceptibility to apoptosis. High level constitutive expression of Bcl-2 or CrmA or incubation with a specific caspase-3 inhibitor inhibited the calcineurin-induced apoptosis. These data indicate that high level constitutive activity of calcineurin predisposes neuronal cells to cytochrome c/caspase-3 dependent apoptosis even under sublethal conditions.
 ...
PMID:High level calcineurin activity predisposes neuronal cells to apoptosis. 1056 26


1 2 3 4 Next >>