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)

Cytotoxic drugs currently remain as the basis for the chemotherapy of metastatic cancer. Why they fail to kill sufficient tumour cells in the major human solid cancers, such as the carcinomas, is suggested in this review to be due to the inherent inability of these cells to engage apoptosis after drug-induced damage. As a paradigm for drug resistant cancers, the resistance of bladder carcinoma cell lines to DNA damaging drugs is described here in terms of their response to the topoisomerase II poison etoposide. 60%-70% of bladder carcinomas have mutant p53; this can prevent the detection of and response to DNA damage. In vitro studies with a bladder carcinoma cell line containing a wild type p53 showed that it underwent a G1 checkpoint after etoposide, potentially allowing DNA damage repair, as well as apoptosis. In lines with mutant or non-functional p53 there is no checkpoint and no apoptosis. All lines showed constitutive expression of bcl-2 and bcl-XL (the suppressors of apoptosis) with low and non-inducible levels of bax (a promoter of apoptosis). Taken together, this menu of gene expression is more favourable to survival than apoptosis after the imposition of drug-induced DNA damage and may contribute to their inherent drug resistance.
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PMID:Apoptosis and cancer chemotherapy. 895 Apr 79

Sphingolipid metabolites are important regulators of cell growth and differentiation. Recent studies have suggested that sphingosine-1-phosphate, a biologically active sphingolipid metabolite, acts as a crucial messenger in apoptosis. In the present work, we examined the expression levels of the members of the bcl-2-related gene family to determine their roles in sphingosine-1-phosphate-induced apoptosis is human hepatoma cells. Our results indicate that sphinogosine-1-phosphate-induced apoptosis is associated with enhanced expression of Bax protein. Moreover, the regulation of bax gene expression by sphingosine-1-phosphate is independent of the p53 tumor suppressor.
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PMID:Induction of apoptosis by sphingosine-1-phosphate in human hepatoma cells is associated with enhanced expression of bax gene product. 895 76

The Apo-1/Fas (CD95) antigen is known to be involved in the process of T cell-mediated target cell killing and has recently been shown to be expressed on myeloma cell lines and native malignant plasma cells. Several cytokines have been reported to interfere with spontaneous and even Apo-1/Fas-induced apoptosis, but no attempt has been made yet to investigate these interactions and the possible underlying mechanisms in myeloma cells. Since in myeloma patients Interferon (IFN)-alpha2 displays a profound therapeutic effect in vivo, which is usually attributed to its growth inhibitory and/or immunomodulatory capacity, we set out to study the potential interference of IFN-alpha2 with Apo-1/Fas-induced apoptosis. Contrary to expectations, IFN-alpha2 reduced the degree of apoptosis caused by the treatment of five Apo-1/Fas-sensitive myeloma cell lines with a Fas monoclonal antibody (mAb). Simultaneous application of IFN-alpha2 and Fas mAb was superior to the prolonged (i.e. >8 h) preincubation with the cytokine as far as inhibition of Apo-1/Fas-induced apoptosis was concerned. This effect of IFN-alpha2 was neither explained by a down-regulation of the Apo-1/Fas receptor nor caused by modulation of the expression levels of c-myc, bcl-2-, bcl-xL, bax- or p53 genes. IFN-alpha2 did not alter the Apo-1/Fas-induced activity of Mitogen-activated protein kinase (MAPK) 1 and did not inhibit the Apo-1/Fas-mediated proteolytic cleavage of ADP-ribosyltransferase, a substrate of Interleukin-beta1 converting enzyme (ICE) and homologues. However, activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) mimicked the effects of IFN-alpha2. Furthermore, the bis-indolylmaleimide GF 109203X, a specific inhibitor of PKC, inhibited the effect of PMA as well as that of IFN-alpha2 on Apo-1/Fas-induced apoptosis. These results point to a PKC-dependent mechanism of transient interaction between the intracellular signaling along the IFN-alpha2 and the Apo-1/Fas pathway (downstream of MAPK signaling as well as of ICE homologues), which becomes exhausted by prolonged stimulation with the cytokine. According to our data IFN-alpha2, applied continuously and in high doses resembling the therapeutic situation in vivo, inhibits myeloma growth. However, based on the observed inhibitory effect of IFN-alpha2 on Apo-1/Fas-induced apoptosis, a partial inhibition of the natural immune surveillance on myeloma cells by endogenous IFN-alpha2 present in the bone marrow microenvironment of this malignancy should be investigated.
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PMID:Modulation of Apo-1/Fas (CD95)-induced programmed cell death in myeloma cells by interferon-alpha 2. 897 13

Expression of the adenovirus E1A oncogene stimulates both cell proliferation and p53-dependent apoptosis in rodent cells. p53 implements apoptosis in all or in part through transcriptional activation of bax, the product of which promotes cell death. The adenovirus E1B 19K product is homologous in sequence and in function to Bcl-2, both of which bind to and inhibit the activity of Bax and thereby suppress apoptosis. The E1B 19K protein also interacts with the nuclear lamins, but the role of this interaction in the regulation of apoptosis is not known. Lamins are, however, substrates for members of the interleukin-1 beta-converting enzyme (ICE) family of cysteine proteases that are activated during apoptosis and function downstream of Bcl-2 in the cell death pathway. lamins are degraded during E1A-induced p53-dependent apoptosis. Lamin A and C are cleaved into 47- and 37-kD fragments, respectively, and the site of proteolysis is mapped to a conserved aspartic acid residue at position 230. The cleavage of lamins during apoptosis is consistent with the activation of an ICE-related cysteine protease down-stream of p53. No lamin protease activity was detected in cells expressing the E1B 19K protein, indicating that 19K functions upstream of protease activation in inhibiting apoptosis. Substitution of the aspartic acid at the cleavage site produced a mutant lamin protein that was resistant to proteolysis both in vitro and in vivo. Expression of uncleavable mutant lamin A or B attenuated apoptosis, delaying cell death and the associated DNA fragmentation by 12 h. Mutant lamin expressing cells failed to show the signs of chromatin condensation and nuclear shrinkage typical of cell death by apoptosis. Instead, the nuclear envelope collapsed and the nuclear lamina remained intact. However, the late stage of apoptosis was morphologically unaltered and formation of apoptotic bodies was evident. Thus, lamin breakdown by proteolytic degradation facilitates the nuclear events of apoptosis perhaps by facilitating nuclear breakdown.
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PMID:Lamin proteolysis facilitates nuclear events during apoptosis. 897 14

The tumor suppressor protein p53 is phosphorylated at multiple sites in the amino-terminal transactivation domain and at several sites in the carboxy-terminal region. Phosphorylation appears to modulate its DNA binding activity. Here we demonstrate that phosphorylation of p53 also modulates its transcriptional activity. Okadaic acid treatment of cells resulted in enhanced phosphorylation of p53 and concomitantly in enhanced transactivation of an mdm2 promoter-linked luciferase reporter gene. This effect was cell type specific, however, since transactivation was enhanced in rat and mouse fibroblasts but reduced in the human Saos-2 cell line. Moreover, the effect was dependent on the promoter. In rat cells transcription from the mdm2, waf1 (cip1) and bax gene promoters, and the artificial PG13 promoter was enhanced by okadaic acid treatment whereas that from the cyclin G promoter was reduced. When various phosphorylation site mutants of p53 were tested for transactivation of these promoters, they behaved differently. Amino-terminal mutants exhibited reduced transcriptional activities on mdm2, waf1 and cyclin G promoters but enhanced activities with bax and PG13 promoters. On the other hand, a mutant at the cdk phosphorylation site, A313, showed reduced activity with mdm2 and waf1 promoters but enhanced activity with the cyclin G promoter, and finally, mutant A390 exhibited enhanced activity on waf1 and bax promoters, but reduced activity on the cyclin G promoter. These results suggest that phosphorylation of p53 may have different effects on its transcriptional activity, depending on the cellular environment and the particular response element. Moreover, both, amino- and carboxy-terminal phosphorylation sites seem to be involved in modulating the DNA-binding and the transactivation activities.
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PMID:Differential effects of phosphorylation of rat p53 on transactivation of promoters derived from different p53 responsive genes. 900 Jan 27

Recent reports have demonstrated that prostaglandin F2alpha-induced generation of reactive oxygen species or their intermediates inhibits progesterone synthesis and may also serve as a trigger for apoptosis in the corpus luteum (CL). BCL-2, an inhibitor of apoptosis in a wide variety of cell types, has been reported to prevent oxidative stress-induced cell death. Thus, the present studies were conducted to determine whether levels of mRNA encoding BCL-2 and related members of this gene family (BAX and BCL-Xshort, which induce apoptosis; BCL-Xlong, a BCL-2 homologue that prevents apoptosis) differed in functional (Day 21 of pregnancy) versus regressed (Day 21 of the estrous cycle) CL in the bovine ovary. Levels of mRNAs encoding p53, a transcriptional regulator of the bcl-2 and bax genes, and interleukin-1beta-converting enzyme (ICE), a protein recently implicated in the induction of apoptosis whose expression may be enhanced by oxidative stress, were also assessed. Partial cDNA clones encoding bovine bax, bcl-x, p53, and Ice were isolated using the reverse transcriptase-polymerase chain reaction (RT-PCR) technique with total RNA prepared from functional or regressed CL. A bovine bcl-2 cDNA could not be isolated from luteal tissue RNA despite the use of several primer pairs for amplification. Total RNA was then extracted from functional or regressed CL and analyzed by Northern blot analysis. The occurrence of apoptosis in regressed CL, as evidenced by the presence of internucleosomal DNA cleavage, was associated with a significant increase in both bax and Ice mRNA levels as compared with levels of bax and Ice expression in functional CL (p < 0.05, n = 3). There were no significant differences in bcl-x or p53 mRNA levels in functional versus regressed CL. Analysis of bcl-x mRNA by RT-PCR revealed that the long form was the primary, if not only, mRNA expressed in functional and regressed bovine luteal tissue. On the basis of data that increased expression of bax is associated with, and may be required for, apoptosis in ovarian granulosa cells and germ cells, we propose that BAX may play a similar role in apoptosis induction during luteal regression. Moreover, the increased Ice mRNA levels in regressed CL provides the first evidence that the ICE family of death proteases may be involved in luteolysis.
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PMID:Increased bax and interleukin-1beta-converting enzyme messenger ribonucleic acid levels coincide with apoptosis in the bovine corpus luteum during structural regression. 900 48

The tumor suppressor gene p53 has been implicated in the induction of apoptosis in dividing cells. We now show that overexpression of p53 using an adenoviral vector in cultured rat hippocampal pyramidal neurons causes widespread neuronal death with features typical of apoptosis. p53 overexpression did not induce p21, bax, or mdm2 in neurons. X-irradiation of hippocampal neurons induced p53 immunoreactivity and cell death associated with features typical of apoptosis. Overexpression of a constitutively active nonphosphorylatable form of the retinoblastoma gene product blocked x-irradiation-induced neuronal death. However, overexpression of the cyclin-dependent kinase inhibitor p21 did not. Treatment of neurons with transforming growth factor-beta1 protected them from x-irradiation. These results are consistent with a role for p53 in nerve cell death that is distinct from its actions relating to cell cycle arrest.
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PMID:p53 expression induces apoptosis in hippocampal pyramidal neuron cultures. 900 81

The protein p53 is a key tumour-suppressor, as evidenced by its frequent inactivation in human cancers. Animal models have indicated that attenuation of p53-dependent cell death (apoptosis) can contribute to both the initiation and progression of cancer, but the molecular mechanisms are unknown. Although p53-mediated transcriptional activation is one possible explanation, none of the known p53-responsive genes has been shown to function in p53-dependent apoptosis. Here we test the role of the death-promoting gene bax in a transgenic mouse brain tumour, a model in which p53-mediated apoptosis attenuates tumour growth. Inactivation of p53 causes a dramatic acceleration of tumour growth owing to a reduction in apoptosis of over ninety per cent. We show that p53-dependent expression of bax is induced in slow-growing apoptotic tumours. Moreover, tumour growth is accelerated and apoptosis drops by fifty per cent in Bax-deficient mice, indicating that it is required for a full p53-mediated response. To our knowledge this is the first demonstration that Bax acts as a tumour suppressor, and our findings indicate that Bax could be a component of the p53-mediated apoptotic response in this system.
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PMID:Bax suppresses tumorigenesis and stimulates apoptosis in vivo. 902 62

Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries but the clinical presentation and rate of disease progression are highly variable. When treatment is required the most commonly used therapy is the nitrogen mustard alkylating agent, chlorambucil (CLB), with or without prednisone. Although CLB has been used in the treatment of CLL for forty years the exact mechanism of action of this agent in CLL is still unclear. Studies in proliferating model tumor systems have demonstrated that CLB can bind to a variety of cellular structures such as membranes, RNA, proteins and DNA; however, DNA crosslinking appears to be most important for antitumor activity in these systems. In addition, a number of different mechanisms can contribute to CLB resistance in these tumor models including increased drug metabolism, DNA repair and CLB detoxification resulting from elevated levels of glutathione (GSH) and glutathione S-transferase (GST) activity. However, unlike tumor models in vitro, CLL cells are generally not proliferating and studies in CLL cells have raised questions about the hypothesis that DNA crosslinking is the major mechanism of antitumor action for CLB in this disease. CLB induces apoptosis in CLL cells and this appears to correlate with the clinical effects of this agent. Thus, alkylation of cellular targets other than DNA, which can also induce apoptosis, may contribute to the activity of CLB. Alterations in genes such as p53, mdm-2, bcl-2 and bax which control entry into apoptosis may cause drug resistance. Loss of wild-type p53 by mutation or deletion occurs in 10 to 15% of CLL patients and appears to correlate strongly with poor clinical response to CLB. The induction of apoptosis by CLB is paralleled by an increase in P53 and Mdm-2 but this increase in not observed in patients with p53 mutations indicating that with high drug concentrations CLB can produce cell death through P53 independent pathways. The level of Mdm-2 mRNA in the CLL cells is not a useful predictor of drug sensitivity. In addition, although Bax and Bcl-2 are important regulators of apoptosis and the levels of these proteins are elevated in CLL cells compared with normal B cells, the levels of Bax and Bcl-2, or the Bax:Bcl-2 ratio, are not important determinants of drug sensitivity in this leukemia. Finally, whereas CLB and nucleoside analogs may produce cell death in CLL by a P53 dependent pathway other agents, such as dexamethasone or vincristine, may act through P53-independent pathways.
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PMID:Chlorambucil in chronic lymphocytic leukemia: mechanism of action. 903 Oct 99

Nine human ovarian cancer cell lines that express wild-type (wt) or mutated p53 were used to evaluate the cytotoxicity induced by paclitaxel. The IC50 calculated in the five mutated p53-expressing cell lines was not different from the four wt p53-expressing cell lines. The introduction of wt p53, by using a temperature-sensitive mutant murine p53 or the human p53 under the control of a tetracycline-dependent promoter, did not change the cytotoxicity of paclitaxel as compared to mock-transfected cells. By using for each cell line the paclitaxel IC50, we found that these concentrations were sufficient to induce an increase in p53 levels in all of the four wt p53-expressing cells, whereas in the mutated p53-expressing cells, the levels were unaffected. This increase in p53 levels led to an increase in the mRNA and protein levels of p53 downstream genes (WAF1, GADD45, and bax). In none of the cell lines examined was paclitaxel able to induce apoptosis, evaluated by terminal deoxynucleotidyl transferase-mediated nick end labeling staining and filter binding assay at concentrations closed to the IC50. By increasing the concentration of paclitaxel in the filter binding assay, we could see fragmentation of DNA in the different cell lines. We conclude that the presence of p53 is not a determinant for the cytotoxicity induced by paclitaxel in human ovarian cancer cell lines. Differences in the activation of p53 downstream genes could be observed in wt versus mutated p53-expressing cells, but this does not account either for a differential induction of apoptosis or for a change in cytotoxicity induced by paclitaxel.
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PMID:p53 status does not affect sensitivity of human ovarian cancer cell lines to paclitaxel. 904 Nov 88


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