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)

Cancers of the microsatellite mutator phenotype (MMP) show exaggerated genomic instability at simple repeat sequences. More than 50 percent (21 out of 41) of human MMP+ colon adenocarcinomas examined were found to have frameshift mutations in a tract of eight deoxyguanosines [(G)8] within BAX, a gene that promotes apoptosis. These mutations were absent in MMP- tumors and were significantly less frequent in (G)8 repeats from other genes. Frameshift mutations were present in both BAX alleles in some MMP+ colon tumor cell lines and in primary tumors. These results suggest that inactivating BAX mutations are selected for during the progression of colorectal MMP+ tumors and that the wild-type BAX gene plays a suppressor role in a p53-independent pathway for colorectal carcinogenesis.
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PMID:Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. 902 77

We have studied the effect of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), a protein kinase inhibitor, on the regulation of apoptosis in the human neuroblastoma cell line, SH-SY5Y. H-7 (20-100 microM) induced apoptosis in these cells characterized by DNA fragmentation and chromatin condensation. Immunoblot analyses were performed with specific antibody against BCL-2, BCL-XS/L, BAX, JUNB, c-JUN, ICH-1L, c-FOS, RB, CDK-2, and p53. H-7 treatment did not significantly alter the level of these proteins with the exception of p53. H-7, but not staurosporine, caused a dramatic nuclear accumulation of p53. The kinetics of nuclear accumulation of p53 correlates well with the kinetics of induction of apoptosis. The effect of H-7 was further assessed in a group of human cell lines. Only cell lines harboring the wild-type p53 gene were responsive to the stimulatory effect of H-7 on nuclear accumulation of p53. Furthermore, cell lines carrying a mutated p53 gene were resistant to the cytotoxic effect of H-7. The ability of H-7 in mediating apoptosis in the SH-SY5Y line expressing a dominant negative mutant of p53 was significantly diminished. Taken together, these data strongly suggest that a p53-dependent mechanism contributes to the cytotoxicity of H-7 in human neuroblastoma cells.
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PMID:1-(5-Isoquinolinesulfonyl)-2-methylpiperazine induces apoptosis in human neuroblastoma cells, SH-SY5Y, through a p53-dependent pathway. 902 Jan 41

When ML-1 human myeloid leukemia cells are exposed to DNA damaging agents, they exhibit dramatic changes in the expression of a variety of gene products. This includes an increase in p53 (wild-type), a decrease in BCL2, a p53-dependent increase in the BCL2 family member BAX, and increases in Growth Arrest and DNA Damage-inducible (GADD) genes such as GADD45; these changes occur as early events in a sequence that culminates in DNA damage-induced apoptosis. DNA damaging agents have now been tested for effects on expression of another BCL2 family member, MCL1, a gene expressed during ML-1 cell differentiation. Expression of MCL1 was found to increase upon exposure of ML-1 cells to various types of DNA damaging agents, including ionizing radiation, ultraviolet radiation, and alkylating drugs. The increase in MCL1 occurred rapidly and was transient, levels of the MCL1 mRNA being elevated within 4 h and having returned to near baseline within 24 h. An increase in the Mcl1 protein was also seen, with the maximal increase occurring at an intermediate dose of IR (5 Gray) and lesser increases occurring at either lower or higher doses. The increase in expression of MCL1 was further studied using a panel of human cell lines that includes cells containing or not containing alterations in p53 as well as cells sensitive or insensitive to the apoptosis-inducing effects of DNA damage. The DNA damage-induced increase in MCL1 mRNA did not depend upon p53 as it was seen in cells lacking functional p53. However, the increase did depend upon susceptibility to apoptosis as it was not seen in cells insensitive to apoptosis-induction by DNA damaging agents. These findings demonstrate that cytotoxic DNA damage causes an increase in the expression of MCL1 along with increases in GADD45 and BAX and a decrease in BCL2. Furthermore, while the increase in GADD45 is seen both in cells that undergo growth arrest and in cells that undergo apoptosis in response to DNA damage, alterations in the profile of expression of BCL2 family members occur exclusively in cells that undergo the apoptotic response, with some family members increasing through p53-dependent (BAX) and others through p53-independent (MCL1) pathways. Overall, expression MCL1 can increase during the induction of cell death as well as during the induction of differentiation.
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PMID:Induction of BCL2 family member MCL1 as an early response to DNA damage. 907 Jun 51

The mammalian cellular response to genotoxic stress is a complex process involving many known and probably many as yet unknown genes. Induction of the human DNA damage- and growth arrest-inducible gene, GADD34, by ionizing radiation was only seen in certain cell lines and correlated with apoptosis following ionizing radiation. In addition, the kinetics and dose response of GADD34 to ionizing radiation closely paralleled that of the apoptosis inhibitor, BAX. However, unlike BAX, the GADD34 response was independent of cellular p53 status. The carboxyl terminus of GADD34 has homology with the carboxyl termini of two viral proteins, one of which is known to prevent apoptosis of virus infected cells. The association of GADD34 expression with certain types of apoptosis and its homology with a known apoptosis regulator suggests that GADD34 may play a role in apoptosis as well.
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PMID:Mammalian GADD34, an apoptosis- and DNA damage-inducible gene. 915 26

The p53 protein is known to play a central role in mediating G1 arrest or apoptosis in response to ionizing radiation in some cell types. It has been proposed that the link between p53 and induction of apoptosis is provided in part by p53-mediated upregulation of BAX. In this study, we used the human SW626 ovarian cancer cell line, which lacks functional p53, to further investigate the relationship between wildtype p53, BAX, and apoptosis. SW626 cells expressing a temperature sensitive (ts) p53 mutant did not undergo G1 arrest or apoptosis and did not exhibit enhanced sensitivity to radiation at the permissive temperature of 32 degrees C. The tsp53 protein was functional in these cells as evidenced by rapid induction of p21 at 32 degrees C, but not at 37 degrees C. Interestingly, restoration of wildtype p53 function at 32 degrees C was not associated with BAX upregulation. In addition, stable overexpression of BAX in SW626 cells was not capable of enhancing apoptotic cell death in response to radiation. Thus, failure of p53 to upregulate BAX is not the sole reason for its inability to promote radiation-induced apoptosis in SW626 cells. Taken together, our data suggest that neither p53 nor BAX upregulation is sufficient for the induction of apoptosis in response to genotoxic damage in some cell types.
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PMID:Radiation-induced apoptosis is not enhanced by expression of either p53 or BAX in SW626 ovarian cancer cells. 919 Aug 90

p53 is a pivotal regulator of apoptosis but its mechanism of action is obscure. We report that the polyproline (PP) region located between p53's transactivation and DNA binding domains is necessary to induce apoptosis but not cell growth arrest. The PP region was dispensable for DNA binding, inhibition of SAOS-2 tumor cell growth, suppression of E1A + RAS cell transformation, and cell cycle inhibition. A temperature-sensitive dominant inhibitory p53 mutant lacking PP (p53ts deltaPP) retained its ability to cooperate with adenovirus E1A in transformation of primary BRK cells. However, while activation of wt p53 induced apoptosis in E1A + p53ts-transformed cells, activation of p53 deltaPP induced cell cycle arrest but not apoptosis in E1A + p53ts deltaPP-transformed cells. Similarly, PP deletion abolished apoptosis in LoVo colon carcinoma cells, which are killed by wt p53 overexpression. Transactivation was largely unaffected by PP deletion. Significantly, BAX induction was intact, indicating that additional events are required for p53 to induce apoptosis. As a recently described site for familial mutation in at least one breast cancer family, the PP region represents a domain that may be altered in human tumors. We concluded that p53's ability to induce apoptosis is dispensable for inhibiting cell growth and transformation and that the PP region plays a crucial role in apoptotic signaling.
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PMID:The polyproline region of p53 is required to activate apoptosis but not growth arrest. 928 84

Apoptosis of type II pneumocytes has been identified in diffuse alveolar damage (DAD), is associated with p53 and WAF1 expression, and may be of pathogenetic importance. BAX, a homologue of BCL-2, is induced by p53 and is a promoter of apoptosis. The proapoptotic effect of BAX is negatively regulated by its binding with BCL-2. In this study, we sought to investigate that role of BAX and BCL-2 in DAD. We hypothesized that alterations in BAX and BCL-2 expression may be important in determining the susceptibility of type II pneumocytes and interstitial cells to apoptosis. Twenty-eight cases of DAD and 16 control cases (i.e., lung tissues adjacent to resected tumors) were retrieved from the files of the University of Utah and the Armed Forces Institute of Pathology. Immunohistochemical stains were performed with antigen retrieval by microwave using antibodies recognizing BAX and BCL-2. The percentage of positively staining pneumocytes and interstitial cells was estimated in each case to the nearest 10%. BAX expression was markedly increased in pneumocytes and interstitial cells in DAD compared with control lung tissues. In DAD, BAX was identified on an average of 80% of alveolar pneumocytes (range 30 to 100%) and 70% of interstitial cells (range 20 to 90%). In control lungs, BAX was identified on an average of 10% of pneumocytes (range 0 to 20%) but not in interstitial cells. Focal BCL-2 staining was identified in interstitial myofibroblasts in 7 of 25 cases of DAD but was only identified in bronchiolar epithelium of control lungs. These results suggest that the induction of BAX in DAD may enhance the susceptibility of alveolar epithelial cells to apoptosis, whereas BCL-2 expression may contribute to the absence of apoptosis in interstitial myofibroblasts. Expression of BCL-2 in interstitial myofibroblasts may contribute to the development of pulmonary fibrosis in some patients.
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PMID:The potential role of BAX and BCL-2 expression in diffuse alveolar damage. 932 33

Previous studies have shown that the apoptotic response of cells following DNA damage requires p53 expression. Wild-type p53 protein levels increase in response to DNA damage and its growth-suppressive action is thought to be mediated by transcriptional activation of the p21/WAF1/CIP1 gene, the product of which is a potent inhibitor of cyclin-dependent kinases. The mechanism by which elevated p53 levels lead to apoptosis is not known, but is believed to involve transcriptional activation of apoptotic genes, such as BAX. We have studied transformed human cells that constitutively express high levels of the R273H mutant p53, which has been reported to lack transcriptional activation activity. We used the inability to induce the p21/Waf1/Cip1 protein as a marker to verify the lack of transcriptional activation activity. Cells expressing the R273H mutant of p53 do not show an increase in p21/Waf1/Cip1 following irradiation with ionizing or UVB radiation. Surprisingly, these cells are very susceptible to induction of apoptosis by UVB radiation, as seen by the formation of a nucleosomal ladder and the proteolytic cleavage of poly(ADP-ribose) polymerase. This suggests that the R273 mutant p53 can function normally in apoptosis but not in transcriptional activation following DNA damage. Furthermore, an inhibitor of RNA polymerase II is a potent inducer of apoptosis in these cells, demonstrating that transcription is not required for apoptosis and suggesting that stalled RNA polymerase II complexes can initiate apoptosis. Interestingly, proteolytic cleavage of p53 occurs during apoptosis in these cells, generating a 45-kDa fragment and liberating the DNA repair helicase binding domain of p53. We propose that the peptide liberated from the carboxy terminus of p53 may contribute to its apoptotic activity, possibly through interaction with the XPB and XPD DNA helicases.
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PMID:The apoptotic and transcriptional transactivation activities of p53 can be dissociated. 949 57

An exacerbated genomic instability at simple repeated sequences characterizes cancer of the microsatellite mutator phenotype (MMP). The majority of hereditary nonpolyposis colon cancers (HNPCCs) and about 15% of nonselected ("sporadic") gastrointestinal tumors belong to the MMP pathway of tumorigenesis. Colorectal MMP+ and MMP- tumors exhibit fundamental differences in genotype and phenotype. We have shown previously that "sporadic" MMP+ colon cancers exhibit a paradoxical low incidence of somatic mutations in the p53 tumor suppressor gene and the c-K-ras proto-oncogene. On the other hand, gastrointestinal MMP+ cancers frequently harbor frameshift mutations in genes containing mononucleotide repeats. These include the cell growth regulator gene TGFbetaRII and the proapoptotic gene BAX. We have also recently shown the frequent presence of frameshift mutations in (A)8 and (C)8 tracts within the hMSH3 and hMSH6 DNA mismatch repair genes in sporadic colon cancer of the MMP. Here, we describe the nearly identical incidence of somatic frameshift mutations in these genes in a panel of 27 HNPCC MMP+ cancers: 52% in hMSH3 and BAX and 33% in hMSH6. In contrast, no mutations in any of these genes were found in 10 MMP- cancers of HNPCC patients. These results show that the multistep model for the unfolding of the MMP also applies to HNPCC and further illustrate the importance of the escape from apoptosis in the MMP pathway for gastrointestinal cancer. They also underscore the differences in genotype between tumors with and without enhanced microsatellite instability and the similarities in genotype between tumors of the MMP regardless of their hereditary or sporadic nature.
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PMID:Somatic frameshift mutations in DNA mismatch repair and proapoptosis genes in hereditary nonpolyposis colorectal cancer. 950 Apr 62

Malignant gliomas are rather refractory to current therapeutic approaches including surgery, radiotherapy, chemotherapy and immunotherapy. Acquired alterations in the pathways required for apoptotic cell death are thought to be responsible to the failure of glioma to respond to therapy. Here we have examined the expression of several proteins involved in the susceptibility to apoptosis in 20 human gliomas, including the BCL-2 family proteins BCL-2, BCL-X, BAX and MCL-1, as well as p53 and RB. Most gliomas expressed several BCL-2 family proteins. There was good correlation between expression of the functional antagonists, BCL-2/BCL-X and BAX, suggesting that changes in the BCL-2+BCL-X/BAX ratio are not responsible for the differential response of glioma patients to chemotherapy. The immunochemistry data were also analysed in regard to response to therapy and clinical outcome. All patients had cytoreductive surgery and received radiotherapy and nitrosourea-based adjuvant chemotherapy. There was no prominent association of outcome with the expression patterns of p53, RB, BCL-2, BCL-X or BAX. We find, however, that expression of the MCL-1 protein is associated with early tumour recurrence and shorter survival in this group of glioma patients. This preliminary observation will have to be confirmed in a larger independent sample of glioma patients.
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PMID:BCL-2 family protein expression in human malignant glioma: a clinical-pathological correlative study. 956 25


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