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

Infection of cervical epithelial cells with certain high risk HPV genotypes is thought to play an etiologic role in the development of cervical cancer. In particular, HPV type 16 and 18 early protein 6 (E6) is thought to contribute to epithelial transformation by binding to the tumor suppressor protein p53, targeting it for rapid proteolysis, resulting in loss of its cell cycle arrest and apoptosis-inducing activities. Recent data indicate that factors responsible for triggering apoptosis reside in the cytoplasm of cells, and not in the nucleus. In particular, the findings that mitochondria are required in certain cell-free models for induction of apoptosis and that bcl-2 is localized to mitochondria have focused attention on the role of the mitochondrial membrane permeability transition (MPT) in apoptosis. Here we present data to indicate that HPV 16 E6 expression sensitizes cells to MPT-induced apoptosis. We also report that HPV 16 E6 sensitization of cells to MPT-induced apoptosis occurs only in the presence of wildtype (wt) p53 expression. The extent of apoptosis induced by atractyloside (an inducer of the MPT) in normal, temperature-sensitive (ts) p53, and HPV-16 E6 transfected J2-3T3 cells, and the HPV expressing cervical carcinoma cell lines SiHa, Hela and CaSki was determined. C33A cells, which express mutant p53 but not HPV, were also exposed to atractyloside in the presence or absence of HPV 16 E6 expression. Dose-dependent apoptosis induced by atractyloside in normal J2-3T3 cells and cervical carcinoma cells was measured by loss of cell viability, nuclear fragmentation and DNA laddering. The sensitivity of cells to atractyloside-induced apoptosis was found to be: HPV 16 E6-J2-3T3 > CaSki > normal-J2-3T3 cells approximately ts p53-J2-3T3 approximately vector-J2-3T3 cells > Hela > SiHa > C33A approximately C33A 16 E6. Cyclosporin A (CsA), an inhibitor of the MPT, and ICE-I, a protease inhibitor, provided protection against atractyloside-induced apoptosis. These findings indicate that: 1) high risk HPV 16 E6 protein is capable of sensitizing cells to apoptosis; 2) HPV 16 E6 sensitization of cells to atractyloside-induced apoptosis occurs in a p53-dependent fashion; 3) the target of HPV 16 E6 sensitization of cells to atractyloside-induced apoptosis is the mitochondria; and 4) HPV 16 E6 sensitization of cells to atroctycoside-induced apoptosis involves an ICE-like protease-sensitive mechanism, regulating the onset of the MPT. These findings constitute the first evidence that mitochondria play a role in HPV 16 E6 modulation of apoptosis.
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PMID:Human papillomavirus (HPV) 16 E6 sensitizes cells to atractyloside-induced apoptosis: role of p53, ICE-like proteases and the mitochondrial permeability transition. 921 25

AIDS-related small noncleaved cell lymphoma (AIDS-SNCCL) includes Burkitt's lymphoma (BL) and high-grade B-cell Burkitt-like lymphoma (BLL). Due to the marked polymorphism of AIDS-related non-Hodgkin's lymphomas (AIDS-NHL), the morphologic distinction between these two types of lymphomas is frequently controversial, although it may bear clinical relevance. Although the molecular features of AIDS-BL have been clarified to a certain extent, the genetic peculiarities of AIDS-BLL have not been investigated in detail. In this study we have compared morphologic and genetic features of AIDS-BL and AIDS-BLL in a blind coded fashion. Molecular studies were focused on the genetic lesions known to be implicated in AIDS-NHL, including alterations of c-MYC, BCL-6, p53, deletions of 6q, as well as infection by EBV and HHV-8. Alterations of c-MYC occurred in 10/10 AIDS-BL, whereas they were restricted to 2/10 AIDS-BLL (P < 0.01). Mutations of p53 were present in 5/10 AIDS-BL, whereas they were consistently absent among AIDS-BLL (n = 10; P < 0.05). Infection by EBV occurred in 30% of both AIDS-BL and AIDS-BLL. Rearrangements of BCL-6, deletions of 6q and infection by HHV-8 scored consistently negative in both AIDS-BL and AIDS-BLL. Based on the genetic lesions tested, the molecular profile of AIDS-BLL appears to be closer to that of AIDS-related diffuse large cell lymphoma (AIDS-DLCL) than to that of AIDS-BL. In contrast to AIDS-BLL however, AIDS-DLCL carried rearrangements of BCL-6 in a fraction of cases (2/9). This study, the largest of its kind reported so far, suggests that AIDS-BL and AIDS-BLL have a different molecular pathogenesis and that characterization of genetic lesions may help to distinguish between these two lymphomas.
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PMID:Genetic heterogeneity of AIDS-related small non-cleaved cell lymphoma. 933 31

The p21WAF1/CIP1 gene, which encodes a cyclin-dependent kinase inhibitor, may be critical for tumor suppressor gene p53-induced cell cycle arrest. The p53 gene is known to regulate G1 checkpoint, which can either induce G1 arrest or initiate apoptosis. To directly examine the role of p21WAF1/CIP1 in the control of p53 function, we have introduced human p21WAF1/CIP1 gene into a p53-deficient human non-small cell lung cancer cell line H1299 using a p21WAF1/CIP1-expressing adenoviral vector (AdCMVp21). Infection with AdCMVp21 resulted in high levels of p21WAF1/CIP1 expression and significantly suppressed the growth of H1299 cells through the G1 arrest of the cell cycle. In contrast, transient expression of the wild-type p53 gene by a recombinant adenoviral vector (AdCMVp53) in H1299 cells induced apoptotic cell death and resulted in a rapid loss of cell viability. We then examined the effects of combined infection with AdCMVp21 and AdCMVp53 on H1299 cells to explore the dominant function of these molecules. Interestingly, introduction of exogenous p53 overcame p21WAF1/CIP1-mediated cell cycle arrest at G1 and induced apoptosis, although viral-transduced p21WAF1/CIP1 expression level was unaffected. These observations suggest that p53 expression converts a p21WAF1/CIP1-mediated growth arrest into apoptosis. The result was repeated with two additional human colon adenocarcinoma cell lines with the different p53 status, mutant p53-expressing DLD-1 and wild-type p53-expressing LoVo, suggesting that this phemonenon is a general event among human cancer cells. Thus, p53-mediated apoptotic pathway is dominant over the growth arrest pathway, indicating that p53 may be an essential upstream mediator of p21WAF1/CIP1 in the regulation of a cell process leading either to growth arrest or to apoptotic suicide.
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PMID:p53 expression overcomes p21WAF1/CIP1-mediated G1 arrest and induces apoptosis in human cancer cells. 936 36

Infection with human cytomegalovirus (HCMV) is a common and generally asymptomatic affection in childhood. Its role in neuroblastoma (NB) patients has not yet been elucidated. As evidence grows that HCMV interacts with apoptotic signaling due to the interaction of HCMV gene products with cellular proteins of apoptotic pathways, we used human NB cell line UKF-NB-2 persistently infected with HCMV strain AD169 to study the effects of long-term HCMV infection on programmed cell death of neuroectodermal tumor cells. The cells designated UKF-NB-2AD169 continued to produce infectious virus in successive subcultures over a period of more than 1 year. Up to 20% of cells expressed viral genes or produced infectious virus after initiation of infection. UKF-NB-2AD169 cells were significantly less sensitive to the cytotoxic agents cisplatinum and etoposide than parental (noninfected) UKF-NB-2 cells. These effects were associated with decreased ability of UKF-NB-2AD169 cells to undergo apoptosis and continuous viral replication. UKF-NB-2AD169 cells showed increased levels of antiapoptosis Bcl-2 protein (up to 12-fold), whereas expression of p53 and c-myc was not changed. Treatment of UKF-NB-2AD169 cells with ganciclovir, abolishing virus production, reestablished sensitivity to chemotherapy, lowered Bcl-2 expression, and facilitated inducibility of apoptosis to the level of the parental cell line. The results demonstrate that persistent HCMV infection confers resistance to cytotoxic agents on neuroectodermal tumor cells and protects from apoptosis, probably due to increased levels of Bcl-2 protein. Hence, it is conceivable that HCMV infection before or during tumorigenesis may contribute in some NB patients to failure of therapy.
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PMID:Persistent human cytomegalovirus infection induces drug resistance and alteration of programmed cell death in human neuroblastoma cells. 944 19

It has recently been shown that an adenovirus mutant lacking expression of the large E1B protein (deltaE1B) selectively replicates in p53 deficient cells. However, apart from the large E1B protein the adenovirus early region encodes the E1A and E4orf6 proteins which also have been reported to affect p53 expression as well as its functioning. After infection with wild-type adenovirus we observed a dramatic decrease in wild-type p53 expression while no down-regulation of p53 could be detected after infection with the deltaE1B virus. The different effects of the wild-type and deltaE1B adenovirus on p53 expression were not only found in cells expressing wild-type p53 but were also observed when tumor cells expressing highly stabilized mutant p53 were infected with these two viruses. Infection with different adenovirus mutants indicated the importance of a direct interaction between p53 and the large E1B protein for reduced p53 expression after infection. Moreover, coexpression of the E4orf6 protein was found to be required for this phenomenon, while expression of E1A is dispensable. In addition, we provide evidence that p53 is actively degraded in wild-type adenovirus-infected cells but not in deltaE1B-infected cells.
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PMID:The large E1B protein together with the E4orf6 protein target p53 for active degradation in adenovirus infected cells. 946 60

Two human herpesviruses, HHV-6 and HHV-7, recently identified and closely related, were studied for their influence on cellular apoptosis and proliferation. Infection was monitored by viral DNA--and antigen expression. Apoptosis and cell proliferation were determined by immunocytological techniques and the markers p53, p21WAF/Cip, Bax, Bak, Bcl-2, cyclin D1 and PCNA, and also screened for signal transduction indicators such as c-H-ras, c-fos and raf-1. Cell differentiation and function was monitored by determining cell membrane receptors including Fas and CD specificities, and by ELISA tests for interleukin production. Both HHV-6 and HHV-7 readily infected their target cells, yet virus antigen expression and virus replication were less active in HHV-7 infection. Both viruses also induced GM-CFS production. Cell differentiation in terms of CD receptor expression was more pronounced in HHV-6 than in HHV-7 infection. No differences were found in the activity of signal transduction factors. There were quantitative differences in the activation of p53, Bax, p21WAF and Bcl-2 in HHV 6-infected CBC as compared to HHV-7 infection supporting the apoptosis cycle. CyclinD1 activity remained at lower levels in HHV-7 infected CBC, yet was high in similarly infected transformed SupT1 cells. In contrast, HHV-6 supported rather the p53/p21WAF apoptosis pathway in both untransformed CBC and transformed HSB1 cells. Both herpesviruses, HHV-6 and HHV-7, thus possessed similar biological activities in cultures of non-transformed susceptible cells, although with certain quantitative differences. The data reported here may further support the notion that HHV-7 is less active in inducing apoptosis thus favoring continued cell proliferation. The mechanism by which these viruses interfere with the network control of cell proliferation, differentiation and apoptosis appear more complicated than shown here and therefore afford a more detailed study, including a more sensitive technology than immunohistology.
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PMID:In vitro cytobiological effects of human herpesviruses 6 and 7: immunohistological monitoring of apoptosis, differentiation and cell proliferation. 949 80

Infection of human cells with adenovirus 12 (Ad12), but not Ad2 or 5, induces four specific sites of metaphase chromosome fragility: the U1 small nuclear RNA (snRNA) genes (the RNU1 locus), the U2 snRNA genes (RNU2), the U1 snRNA pseudogenes (PSU1) and the 5S rRNA genes (RN5S). Significantly, each of these sites corresponds to a multigene family encoding a small, abundant structural RNA. We and others have shown previously that Ad12-induced fragility of the RNU2 locus requires U2 snRNA promoter elements, viral early functions and p53 function, but not viral replication or integration, Rb function or chromosomal sequences flanking the RNU2 locus. Remarkably, we now find that very low doses of actinomycin D (5-50 ng/ml) can phenocopy Ad12 infection: metaphase fragility of the RNU1 and RNU2 loci is induced specifically in the absence of virus, and induction also requires U2 promoter elements and p53 function. Concurrently, it has been found by others that treatment with cytosine arabinoside (araC), but not aphidicolin, can also phenocopy Ad12 infection. We propose that Ad12 infection, actinomycin D and araC all induce a similar or identical global damage arrest signal (perhaps a modification or altered conformation of p53) that preferentially interferes with metaphase condensation of the RNU1 and RNU2 loci. The RNU1 and RNU2 loci could be especially sensitive to this global signal either because specialized U snRNA transcription factors interact uniquely with the signal, or because the high concentration of short, active transcription units hinders chromatin condensation.
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PMID:Metaphase fragility of the human RNU1 and RNU2 loci is induced by actinomycin D through a p53-dependent pathway. 949 13

Reconstitution of the p53-dependent apoptotic pathway by gene transfer of a recombinant wild-type p53 minigene leads to rapid apoptotic cell death in breast and other cancer cell types expressing null or mutant p53. Tumour cells expressing wild-type p53 have been reported to be more resistant to this treatment strategy, presumably as a result of mutations in downstream regulators of p53-dependent apoptotic signalling. The MCF-7 breast cancer cell line is representative of this class of tumour cell. Our recent observation of a p53-dependent apoptotic response following adenovirus-mediated HSV thymidine kinase gene transfer and gancyclovir treatment led us to reexamine recombinant p53 cytotoxicity in MCF-7 cells. Infection with a recombinant adenovirus expressing wild-type p53 resulted in a dramatic increase in p53 protein levels and was accompanied by an increase in p21WAF/CIP1 protein levels and G1 arrest within 24 hours post-infection. A significant decrease in MCF-7 cell viability was first observed at 5 days post-infection and coincided with the appearance of morphological and biochemical changes consistent with apoptotic cell death. By day 7 post-treatment, cell viability decreased to 45% and clonogenic survival was reduced to 12% of controls. The results demonstrate that persistent, high level expression of recombinant p53 can induce programmed cell death in MCF-7 cells. While the mechanism by which p53 overexpression overcomes the defect in downstream apoptotic signalling is not clear, our data suggests that this treatment strategy may be beneficial for the class of tumour cells represented by the MCF-7 cell line.
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PMID:Therapeutic potential of recombinant p53 overexpression in breast cancer cells expressing endogenous wild-type p53. 959 74

Adenovirus infection of CD34+ hematopoietic stem/progenitor cells is dependent on the multiplicity of infection (MOI), time of incubation, the volume in which the co-incubation occurs and the presence or absence of growth factors. Studies revealed that a brief co-incubation (1-8 hours), resulted in low levels of transgene expression, suggesting that adenovirus infection of CD34+ cells occurs slowly, and optimal transduction requires a 24 hour exposure to adenovirus. Infection by Ad/beta-gal or Ad/p53 at a MOI of 500:1 provided a high transduction efficiency but inhibited hematopoietic function. However, treatment at a MOI of 50-100 resulted in efficient transduction (10.7-15.7% positive) without detectable toxicity. Secondary proof of adenovirus transgene expression was demonstrated by detection of mRNA for p53 in Ad/p53 infected stem cells. We conclude that a 24 hour exposure to recombinant adenovirus encoding p53 or beta-gal, at a MOI of 50-100 is optimal for in vitro gene transfer to BM cells and has no significant effect on hematopoietic function. Adenovirus-mediated transduction of BM cells can also be modulated by growth factors (IL-3, GM-CSF and G-CSF) with improved gene delivery and maintenance of hematopoietic function. In summary, adenovirus vectors can be used to transiently transduce stem cells, and conditions have been defined to maximize expression and limit inhibitory effects on CD34+ cells. These data support continued investigation of this vector for local cytokine delivery and purging of stem cell products.
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PMID:Enhancement of adenovirus-mediated gene transfer to human bone marrow cells. 964 58

We investigated the p53 status and the ability of exogenous wildtype (wt) p53 to affect chemosensitivity in three anaplastic thyroid carcinoma cell lines (BHT-101, SW-1736, and KAT-4). All three cell lines had nonfunctional p53. Treatment with mitomycin C or adriamycin did not result in accumulation of p53 or induction of p21WAF1/CIP1 or Mdm-2 and did not cause Rb dephosphorylation. BHT-101 and KAT-4 cells had mutant p53. SW-1736 cells were functionally mutant because of marked down-regulation of wt p53 messenger ribonucleic acid, representing a novel mechanism of p53 dysfunction. Infection with a p53-expressing adenovirus (Ad-p53) induced high levels of p21 and Mdm-2 proteins. In BHT-101 cells, induction of p21 and Mdm-2 was evident 10 h after infection. In KAT-4 cells, induction of p21 and Mdm-2 was observed 1 day after infection, and continued to increase over the ensuing 24 h. SW-1736 cells demonstrated intermediate kinetics. Sensitivity to the cytotoxic effect of Ad-p53 paralleled the kinetics of p21/Mdm-2 induction. BHT-101 cells were most sensitive to killing by Ad-p53, with an IC50 of less than 2 multiplicity of infection; SW-1736 cells were intermediate in sensitivity; KAT-4 cells were resistant. All three cell lines became more sensitive to adriamycin after wt p53 expression, with a 10-fold decrease in IC50 values. The latter observation may make a combination of wt p53 and chemotherapeutic drugs an attractive modality for treating anaplastic thyroid cancer.
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PMID:Effects of p53-expressing adenovirus on the chemosensitivity and differentiation of anaplastic thyroid cancer cells. 966 37


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