Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Employing the myeloblastic leukemia M1 cell line, which does not express endogenous p53, and genetically engineered variants, it was recently shown that activation of p53, using a p53 temperature-sensitive mutant transgene (p53ts), resulted in rapid apoptosis that was delayed by high level ectopic expression of bcl-2. In this report, advantage has been taken of these M1 variants to investigate the relationship between p53-mediated G1 arrest and apoptosis. Flow cytometric cell cycle analysis has provided evidence that activation of wild-type (wt) p53 function in M1 cells resulted in the induction of G1 growth arrest; this was clearly seen in the M1p53/bcl-2 cells because of the delay in apoptosis that unmasked p53-induced G1 growth arrest. This finding was further corroborated at the molecular level by analysis of the expression and function of key cell cycle regulatory genes in M1p53 versus M1p53/bcl-2 cells after the activation of wt p53 function; events that take place at early times during the p53-induced G1 arrest occur in both the M1p53 and the M1p53/bcl-2 cells, whereas later events occur only in the M1p53/bcl-2 cells, which undergo delayed apoptosis, thereby allowing the cells to complete G1 arrest. Finally, it was observed that a spectrum of p53 target genes implicated in p53-induced growth suppression and apoptosis were similarly regulated, either induced (gadd45, waf1, mdm2, and bax) or suppressed (c-myc and bcl-2), after activation of wt p53 function in M1p53 and M1p53/bcl-2 cells. Taken together, these findings show that wt p53 can simultaneously induce the genetic programs of both G1 growth arrest and apoptosis within the same cell type, in which the genetic program of cell death can proceed in either G1-arrested (M1p53/bcl-2) or cycling (M1p53) cells. These findings increase our understanding of the functions of p53 as a tumor suppressor and how alterations in these functions could contribute to malignancy.
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PMID:Dissection of the genetic programs of p53-mediated G1 growth arrest and apoptosis: blocking p53-induced apoptosis unmasks G1 arrest. 774 28

Twenty-nine samples from 28 cases of vulvar squamous cell carcinoma, of which 13 fulfilled the criteria of the bowenoid subtype (mean age 45 years, range 31-68) and 16 of the usual subtype of invasive squamous cell carcinoma (ISCC) (mean age 67.5 years, range 34-83) were investigated for human papillomavirus (HPV) DNA, TP53 alterations, and mdm2 and bcl-2 gene product deregulation. Microscopically all the bowenoid subtype cases (group I) showed a high-grade intraepithelial (VIN 3, carcinoma in situ) lesion associated with early invasive carcinoma in six cases and overt invasive carcinoma in one. By contrast, no evidence of early carcinoma was present in the ISCCs (group II). By in situ hybridization and/or Southern blot hybridization or polymerase chain reaction (PCR), HPV DNA was detected in all cases of group I and in four of 16 cases (25%) of group II, two only by Southern blot after PCR. By single-strand conformation polymorphism and immunocytochemistry only wild-type TP53 and absence of detectable p53 product, respectively, were found in all cases of group I, i.e., in high-risk HPV-positive carcinomas, whereas mutations and/or p53 overexpression accounted for 75% in group II, i.e., in mainly HPV-negative carcinomas. The TP53 gene mutations observed in invasive carcinomas were significantly related to node-positive cases (p = 0.04). Taken together and in agreement with in vitro data, these results support the view that an alteration of TP53, gained either by interaction with viral oncoproteins or by somatic mutations, is a crucial event in the pathogenesis of vulvar carcinomas, but that TP53 mutations are mainly associated with disease progression. Finally, a preliminary immunocytochemical analysis seems to speak against the possible involvement of both MDM2 and BCL-2 gene products in the development of vulvar carcinoma.
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PMID:Papillomavirus, p53 alteration, and primary carcinoma of the vulva. 863 79

Two Epstein-Barr virus (EBV)-associated malignancies, nasopharyngeal carcinoma and posttransplant lymphoma, rarely have mutations in the p53 tumor suppressor gene, suggesting that a viral protein interferes with p53 function. The EBV oncogene, LMP1, induces expression of the cellular antiapoptotic genes bcl-2 and A20 and could in this way interfere with p53-mediated apoptosis. Two derivatives of the p53-null epithelial cell line H1299 were prepared, one of which (H1299-p53) stably expressed a temperature-sensitive (ts) p53 protein, and another (H1299-p53+LMP1) which stably expressed both ts-p53 and latent membrane protein 1 (LMP1). At the permissive temperature, the p53 protein in the H1299-p53 cell line transcriptionally activated two of its target genes, the cyclin-dependent kinase inhibitor p21 and the mdm2 gene product, in an LMP1-independent manner. Upon serum withdrawal at the permissive temperature, p53-mediated apoptosis was induced in 50 to 60% of the cells. In the H1299-p53 cell line which stably expressed LMP1, however, only 20 to 25% of the cells underwent apoptosis. While stable expression of LMP1 did not affect levels of bcl-2 family members in these cells, it did induce expression of A20. Stable expression of A20 in the H1299-p53 cell line inhibited p53-mediated apoptosis equivalent to inhibition by LMP1. The induction of A20 may underlie the ability of LMP1 to protect EBV-infected epithelial cells from p53-mediated apoptosis.
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PMID:Epstein-Barr virus latent membrane protein 1 blocks p53-mediated apoptosis through the induction of the A20 gene. 897 Sep 91

We have investigated the immunohistochemical expression of p53, mdm2, p21/waf1 and bcl-2 proteins in 31 thymic epithelial tumours comprising five medullary thymomas (MDT), four mixed thymomas (MT), 12 cortical thymomas (CT), eight predominately cortical thymomas (PCT) and two well-differentiated thymic carcinomas (WDTC). We have found p53, mdm2, p21 and bcl-2 protein expression in 25/31, 8/31, 5/31 and 10/31 thymic epithelial tumours, respectively. Coexpression of p53 and mdm2 proteins was found in eight cases (three CT, four PCT and one WDTC). Five of them were also p21 positive and three p21 negative. Discordant p53+/mdm2-/p21- protein expression was found in 19 cases (three MDT, three MT, nine CT, three PCT and one WDTC). Mdm2 and p21 proteins were not expressed in the absence of p53 protein. Coexpression of bcl-2 and p53 proteins was found in seven cases (three MDT, three MT and one WDTC). Eighteen cases were p53+/bcl-2- (10 CT, seven PCT and one WDTC) and three cases (two MDT and one MT) were bcl-2+/p53-. Our findings indicate that in thymomas, p53 expression is more frequently associated with cortical histotypes while bcl-2 expression is strongly associated with medullary and mixed histotypes. In addition, there is an inverse correlation between p53 and bcl-2 protein expression in thymomas. Coexpression of p53/mdm2/p21 proteins may reflect thymomas with wild-type (wt), p53 gene since mdm2 and p21 proteins are inducible by wt p53 gene. However, in view of previous findings that p53 mutation is an early event in thymomas, the possibility of p53 gene mutation with p53-independent mdm2 and p21 expression should be considered in these cases. Discordant p53+/mdm2-/p21- protein expression may represent thymomas with p53 gene mutations unable to activate expression of mdm2 and p21 proteins.
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PMID:Expression of p53, mdm2, p21/waf1 and bcl-2 proteins in thymomas. 920 59

A murine erythroleukemic cell line (1-2-3) which expresses only the temperature-sensitive mutant p53 gene (Ala-to-Val substitution at codon 135) was established. When these cells were cultured at 32 degrees C, the growth rate was reduced significantly and DNA fragmentation, a typical character of apoptosis, was observed. In this process, p53 migrated from cytoplasm to nucleus and protein complexes binding to the p53-responsive element were detected in nuclear extracts of the cells cultured at 32 degrees C by gel-shift assay and transactivation from the p53-responsive element was detected. The expression of the p21 (waf1/cip1/sdi1), cyclin G and gadd45 genes was increased (about 3 to 4 fold that at 37 degrees C), when the cells were cultured at 32 degrees C. However, the expression of the bax gene was increased slightly (about 1.5 fold that at 37 degrees C) and no significant change was detected in expression of the mdm2 gene. No change in the amount of Fas antigen was observed by flow cytometric analysis. Transcripts of the bcl-2 and fasl gene were not detected in the cells both at 37 degrees C and 32 degrees C. These results suggest that up-regulation of the genes associated with the cell cycle and/or DNA replication, such as p21, cyclinG and gadd45 rather than bax, fas, fasl and bcl-2 may be important for induction of apoptosis of this erythroleukemic cell line by p53.
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PMID:Up-regulation of cell cycle-associated genes by p53 in apoptosis of an erythroleukemic cell line. 920 1

The present study was undertaken to examine the distribution of p53, p21, mdm-2 and bcl-2 protein expression in human colorectal adenocarcinomas in order to obtain combined information about the immunophenotypes characterising these tumours. Formalin-fixed, paraffin-embedded tissue sections from 52 cases of colorectal adenocarcinomas were stained using immunohistochemical methods for the detection of p53, p21/waf1, mdm2 and bcl-2 proteins. P53, p21/waf1, mdm2 and bcl-2 proteins were expressed in 35/52, 45/52, 9/52 and 27/52 cases, respectively. All nine mdm2+ cases expressed p53 and p21 proteins as well. The three patterns observed in p53/p21 expression were: p53+/p21+, p53+/p21- and p53-/p21+ in 28, 7, and 17 cases, respectively. Consequently, p53+/mdm2-/p21+, p53+/mdm-/p21- and p53-/mdm2-/p21+ immunophenotypes were expressed in 19, 7, and 17 cases respectively. Four patterns of p53/bcl2 expression were identified: p53+/bcl2+, 20 cases; p53+/bcl2-, 15 cases; p53-/bcl2+, 7 cases; p53-/bcl2-, 10 cases. It was noteworthy that 9 of the 10 p53-/bcl2-tumours had negative lymph node status. The present results suggest that both p53 dependent and p53-independent induction of p21 expression may be involved in the molecular mechanisms controlling these tumours. High expression of the p53 protein in colorectal carcinomas could be due not only to p53 gene mutations but also to binding to mdm2 protein which leads to p53 protein stabilisation. In addition, tumours with p53-/bcl2- immunophenotype are frequently associated to negative lymph node status and seem to be less aggressive.
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PMID:Immunohistochemical expression of p53, bcl-2, mdm2 and waf1/p21 proteins in colorectal adenocarcinomas. 925 82

This study attempts to define more clearly the morphology and ultrastructure of mummified Hodgkin cells, to determine their incidence in the different histological subtypes of Hodgkin's disease (HD), and to correlate these data with the expression of p53, bcl-2, mdm2, and p21/WAF1. Forty-five cases of primary HD were examined at light and electron microscopic level. DNA strand breaks were detected by the in situ end-labelling (ISEL) and the TdT-mediated dUTP-digoxigenin nick end-labelling (TUNEL) technique. Mummified Hodgkin cells display morphological features that differ from those of classical apoptosis. In contrast to apoptotic cells, mummified Hodgkin and Reed-Sternberg (HRS) cells do not react in the ISEL or TUNEL procedures and maintain the expression of antigens such as CD30 and CD15. The morphology of mummified tissue cells could be simulated by CD95-mediated induction of apoptosis in the Hodgkin cell line HDLM2 if internucleosomal DNA fragmentation was inhibited by zinc ions. The highest incidence of mummified cells was found in the nodular sclerosis and mixed cellularity subtypes, whereas the lowest frequency was observed in nodular paragranuloma. The frequency was independent of p53, bcl-2, p21, and mdm2 expression. p21 and mdm2 immunoreactivity of HRS cells was correlated with p53 status. HRS cells in nodular paragranuloma were virtually negative for p21/WAF1 or bcl-2. Classical apoptotic cells reacting in the TUNEL and ISEL procedures are found in all subtypes of HD and are derived from the non-neoplastic cellular background. In conclusion, mummified Hodgkin cells display features of apoptosis lacking the internucleosomal DNA fragmentation. The pattern of the p53-transactivated genes mdm2 and p21/WAF1 suggests that inactivating mutations of p53 are rare in HD.
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PMID:The mummified Hodgkin cell: cell death in Hodgkin's disease. 934 31

A new category of oncogenes regulating apoptosis, p53 and bcl-2, and the Epstein Barr virus (EBV) latent membrane protein-1 (LMP-1) have been related to Hodgkin's disease (HD) pathogenesis. We attempt to determine p53, mdm2, p21waf-1, bcl-2 and LMP-1 immunohistochemical expression in tissue sections from formalin-fixed, paraffin-embedded lymph node biopsies of pediatric HD. P53 was detected in the nucleus of Reed Sternberg cells and their variants (H-RS) in 68% of the HD cases. However, there was no statistically significant association with either clinical stages or with histological subtypes. P21waf-1, an indirect marker of p53 functional status, showed nuclear labelling of H-RS in all the studied cases. MDM2 co-expressed with p53 in 62% of the cases, suggesting that both proteins regulate one another, in HD by a self regulatory loop. Bcl-2 cytoplasmatic expression in H-RS was demonstrated in 65% of the cases. There was co-expression of bcl-2 and p53 in 51%, but it failed to correlate with a poor prognosis. LMP-1 labelling was shown in 51% of the cases, disclosing a statistically significant association with the under 6-year group (p = 0.005, Fisher's exact test). Since LMP-1 induces the expression of bcl-2 in vitro, the relation of both proteins was analysed and found to co-express in 15/37 cases, with a statistically significant association only in the under 6-year group (p = 0.001, Fisher's exact test). Abnormal accumulation of these oncoproteins in tumour cells could play a role in the pathogenesis of a subset of pediatric HD.
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PMID:Oncogene expression in tumour cells of pediatric Hodgkin's disease in Argentina--correlation with Epstein Barr virus presence. 954 44

Thirty-one cases of small cell lung carcinomas (SCLC) were investigated by immunohistochemistry for the expression of bcl-2, p53 and the wild-type (wt) p53- induced proteins mdm2 and p21/waf1. Bcl-2 protein was detected in 24/31 cases of SCLC(77%) and p53 protein in 13/31 cases (42%). No correlation was found between histological subtype of SCLC and bcl-2 or p53 expression. Comparison between bcl-2 and p53 expression showed that 14/31 cases (45%) were only bcl-2 positive, 3/31 (11%) were only p53 positive, 10/31 (32%) were positive for both proteins and 4/31 (13%) were negative for both proteins. Mdm2 protein was detected in 2/32 SCLC which were also p53 positive. P21 protein was detected in 6/32 SCLC. Four of the p21 positive SCLC were negative for both p53 and mdm2, and two were positive for both p53 and mdm2 proteins. The significant expression of bcl-2 protein in SCLC suggests that bcl-2 may be involved in the pathogenesis of most SCLC by inhibiting apoptosis during neoplastic transformation. The expression of p53 protein in SCLC is likely to be related to underlying p53 gene mutations since these genetic alterations are very frequent in SCLC. This can be supported by our findings that 11/13 p53 positive SCLC were mdm2 and p21 negative. The two cases with p53+/mdm2+/p21+ phenotype may represent tumours with wt p53 gene and p53 protein immunoexpression due to binding to mdm2 protein. The four cases with p53-/mdm2-/p21+ phenotype may represent tumours with p53-independent p21 protein expression. Coexpression of p53 and bcl-2 proteins in a proportion of SCLC suggests that in these tumours p53 doses not maintain its suppressive effect on bcl-2 expression as it has been reported in vitro. Further studies at DNA and RNA level are required to clarify the involvement of bcl-2, p53, mdm2 and waf1 genes in SCLC pathogenesis.
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PMID:Immunohistochemical detection of bcl2, p53, mdm2 and p21/waf1 proteins in small-cell lung carcinomas. 961 83

Thirty-one cases of small cell lung carcinomas (SCLC) were investigated by immunohistochemistry for the expression of bcl-2. P53 and the wild-type (wt) p53-induced proteins mdm2 and p21/waf1. Bcl-2 protein was detected in 24/31 cases of SCLC(77%) and p53 protein in 13/31 cases (42%). No correlation was found between histological subtype of SCLC and bcl-2 or p53 expression. Comparison between bcl-2 and p53 expression showed that 14/31 cases (45%) were only bcl-2 positive, 3/31 (11%) were only p53 positive, 10/31 (32%) were positive for both proteins and 4/31 (13%) were negative for both proteins. Mdm2 protein was detected in 2/32 SCLC which were also p53 positive. P21 protein was detected in 6/32 SCLC. Four of the p21 positive SCLC were negative for both p53 and mdm2, and two were positive for both p53 and mdm2 proteins. The significant expression of bcl-2 protein in SCLC suggests that bcl-2 may be involved in the pathogenesis of most SCLC by inhibiting apoptosis during neoplastic transformation. The expression of p53 protein in SCLC is likely to be related to underlying p53 gene mutations since these genetic alterations are very frequent in SCLC. This can be supported by our findings that 11/13 p53 positive SCLC were mdm2 and p21 negative. The two cases with p53+/mdm2+/p21+ phenotype may represent tumours with wt p53 gene and p53 protein immunoexpression due to binding to mdm2 protein. The four cases with p53-/mdm2-/p21+ phenotype may represent tumours with p53-independent p21 protein expression. Coexpression of p53 and bcl-2 proteins in a proportion of SCLC suggests that in these tumours p53 does not maintain its suppressive effect on bcl-2 expression as has been reported in vitro. Further studies at the DNA and RNA level are required to clarify the involvement of bcl-2, p53, mdm2 and wafl genes in SCLC pathogenesis.
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PMID:Immunohistochemical detection of bcl2, p53, mdm2 and p21/waf1 proteins in small-cell lung carcinomas. 967 91


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