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)

Kaposi's sarcoma-associated herpesvirus (KSHV) has a key etiological role in development of Kaposi's sarcoma (KS). v-Cyclin is a KSHV-encoded homologue to D-type cyclins that associates with cellular cyclin-dependent kinase 6 (CDK6). v-Cyclin promotes S-phase entry of quiescent cells and has been suggested to execute functions of both D- and E-type cyclins. In this study, expression of v-cyclin in cells with elevated levels of CDK6 led to apoptotic cell death after the cells entered S phase. The cell death required the kinase activity of CDK6 because cells expressing a kinase-deficient form of CDK6 did not undergo apoptosis upon v-cyclin expression. Studies on the mechanisms involved in this caspase-3-mediated apoptosis indicated that it was independent of cellular p53 or pRb status, and it was not suppressed by Bcl-2. In contrast, the KSHV-encoded v-Bcl-2 efficiently suppressed v-cyclin-/CDK6-induced apoptosis, demonstrating a marked difference in the antiapoptotic properties of c-Bcl-2 and v-Bcl-2. In KS lesions, high CDK6 expression was confined to a subset of cells, some of which displayed signs of apoptosis. These results suggest that v-cyclin may exert both growth-promoting and apoptotic functions in KS, depending on factors regulating CDK6 and v-Bcl-2 levels.
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PMID:Kaposi's sarcoma-associated herpesvirus-encoded v-cyclin triggers apoptosis in cells with high levels of cyclin-dependent kinase 6. 1051 12

By using flow-cytometric analysis, we examined the involvement of p53, c-Myc, Bcl-2 and Bax in the glutamate-induced cell death in cultured cortical neurons. The activities of caspase-1-like and caspase-3-like proteases were also measured after the glutamate treatment. The apoptosis rate of the cells increased after 12 h and 24 h treatment with glutamate. The temporal profile of p53, c-Myc, Bcl-2, Bax expression and caspases activation after glutamate treatment suggest that Bcl-2, c-Myc and caspase-3 play important roles in the excitotoxic neuronal cell death. The down-regulation of Bcl-2 may be an important early stage event, which may cause the activation of caspase-3. c-Myc is also involved in the process of apoptosis though its precise role remains elusive. bFGF exhibited the capability to antagonize the neuronal apoptosis caused by glutamate. The antiapoptotic potential of bFGF may result from its attenuating effect on the down-regulation of Bcl-2 induced by glutamate and, subsequently, blockade of apoptosis cascade. This may provide a possible explanation for its neuroprotective effect against ischemic cell death.
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PMID:Roles of p53, c-Myc, Bcl-2, Bax and caspases in glutamate-induced neuronal apoptosis and the possible neuroprotective mechanism of basic fibroblast growth factor. 1052 75

In vitro experiments suggest that angiotensin II (Ang II) may cause growth via angiotensin type 1 (AT(1)) receptors and apoptosis via angiotensin type 2 (AT(2)) receptors. To answer the question of whether AT(1) or AT(2) receptor activation could induce apoptosis in the vasculature in vivo, Wistar rats were infused for 7 days with Ang II (120 ng. kg(-1). min(-1) subcutaneously) and treated with the AT(2) receptor antagonist PD 123319 (30 mg. kg(-1). d(-1) subcutaneously) or the AT(1) receptor antagonist losartan (10 mg. kg(-1). d(-1) orally). Apoptosis in thoracic aorta was quantified by radiolabeled DNA laddering and by terminal deoxynucleotide transferase-mediated dUTP nick end-labeling. The expression of p53, bax, bcl-2, and caspase-3, which play critical roles in apoptotic signaling, was examined by Western blot analysis. The mRNA expression of AT(1) and AT(2) receptors was determined by reverse transcription-polymerase chain reaction. The increase in systolic blood pressure and aortic growth induced by Ang II infusion was completely prevented by losartan alone or losartan given with PD 123319, whereas PD 123319 resulted in a greater increase in systolic blood pressure and aortic growth than Ang II alone. Radiolabeled DNA laddering showed that Ang II infusion+/-losartan or PD 123319 significantly increased apoptosis (147+/-8%, 178+/-20%, and 238+/-41%, respectively, P<0.05 compared with control). Expression of bax and active forms of caspase-3 was increased in the Ang II+PD 123319 group, whereas the expression of p53 and bcl-2 was not significantly different in all groups. The expression of AT(1) and AT(2) receptor mRNA was downregulated by losartan and PD 123319, respectively. Thus, when AT(1) or AT(2) receptors are stimulated in vivo, apoptosis is enhanced in the media of blood vessels. In the case of AT(1) receptor stimulation, this may occur secondary to vascular growth and modulate the latter. Both bax and caspase-3 participate in the pathways of apoptosis triggered by in vivo AT(1) receptor stimulation.
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PMID:In vivo study of AT(1) and AT(2) angiotensin receptors in apoptosis in rat blood vessels. 1052 36

Using flow cytometric analysis, we examined the temporal changes of p53, c-Myc, Bcl-2, Bax expression in rat primary cortex neurons after serum deprivation. Activities of caspase-1 and caspase-3 were also measured. Serum deprivation induced apoptosis accompanied by a rapid down-regulation of p53, Bcl-2 and an up-regulation of c-Myc, Bax and caspase-3 activity. Pretreatment with basic fibroblast growth factor prevented the apoptosis with an attenuation of the changes of p53, Bcl-2, Bax levels and caspase-3 activity but had no effect on the change of c-Myc level. These results suggest that serum deprivation induces apoptosis through a signaling pathway involving p53, Bcl-2, Bax, c-Myc and caspase-3. The effect of the basic fibroblast growth factor against apoptosis may result from its capability of blocking the apoptosis cascade.
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PMID:Roles of p53, c-Myc, Bcl-2, Bax and caspases in serum deprivation-induced neuronal apoptosis: a possible neuroprotective mechanism of basic fibroblast growth factor. 1054 28

This study deals with the apoptotic effect exerted on human retinoblastoma Y79 cells by both sodium butyrate and an inhibitor of 26S proteasome [z-Leu-Leu-Leu-CHO (MG132)] and their synergistic effect. Exposure to sodium butyrate (1-4 mM) induced an accumulation of cells in the G2-M phase that was already visible after 24 h of treatment, when morphological and biochemical signs of apoptosis appeared only in a small number of cells (5-10%). Thereafter, the apoptotic effects increased progressively with slow kinetics, reaching a maximum after 72 h of exposure, when they concerned a large fraction of cells (>75% with 4 mM sodium butyrate). Sodium butyrate stimulated the conversion of procaspase-3 into caspase-3 and also induced the cleavage of poly-(ADP-ribose) polymerase and lamin B, two hallmarks of apoptosis. All of the apoptotic signals were suppressed by benzyloxy carbonyl-Val-Ala-Asp-fluoromethylketone (a general inhibitor of caspase activities), whereas acetyl-Asp-Glu-Val-Asp aldehyde, a specific inhibitor of caspase-3 activity, only induced a partial reversion of the apoptotic effects. Sodium butyrate also decreased the Bcl-2 level, whereas it increased the Bax level and stimulated the release of cytochrome c from the mitochondria, an event that was most likely responsible for the activation of caspase-3. Finally, sodium butyrate activated 26S proteasome, the major extralysosomal degradative machinery, which is responsible for the degradation of short-lived proteins. Consequently, the levels of p53, N-myc, and IkappaBalpha (factors that play regulatory roles in apoptosis) diminished, whereas the nuclear level of nuclear factor kappaB concomitantly increased. Treatment of Y79 cells with MG132 induced apoptosis with more rapid kinetics than with sodium butyrate. The effects appeared after 8 h of incubation, reaching a maximum at 24 h, and they were accompanied by increased levels of N-myc, p53, and IkappaBalpha. MG132 also favored the release of cytochrome c from the mitochondria and increased the activity of caspase-3. When Y79 cells were exposed to combinations of sodium butyrate and MG132, the latter compound suppressed the decreasing effect induced by sodium butyrate on the levels of p53, N-myc, and IkappaBalpha and the increasing effect on the nuclear level of nuclear factor kappaB. Moreover, an increase in the level of Bax and an enhancement in the release of cytochrome c from the mitochondria were observed. Clear synergistic effects concerning the activation of both caspase-3 and apoptosis were induced by a combination of suboptimal doses of sodium butyrate and MG132. The results support the conclusion that MG132 potentiates the apoptotic effect of sodium butyrate by suppressing its stimulatory effect on 26S proteasome activity. Synergistic interactions between butyrate and inhibitors of proteasome could represent a new important tool in tumor therapy and, in particular, the treatment of retinoblastoma.
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PMID:The apoptotic effects and synergistic interaction of sodium butyrate and MG132 in human retinoblastoma Y79 cells. 1055 39

In this study, both NIH3T3 and Bcl-2 transfected NIH3T3 cells were examined for their propensity to undergo nitroso compound-induced apoptosis. Bcl-2-expressing NIH3T3 prevented N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)- and S-nitrosoglutathione (GSNO)-induced apoptosis as compared with the control NIH3T3 cells. Flow cytometry revealed that NIH3T3 cells treated with MNNG undergo apoptotic death, which occurred after G2-M arrest in the second cycle of cell proliferation. The mechanism of MNNG-induced NIH3T3 cells apoptosis was observed throughout the activation of caspase-3 protease, PARP degradation and cytochrome c release; it was independent of p53 activation. Glutathione-S-transferanse pi (GST pi) is activated through the transcription activation of antioxidant response element (ARE) during MNNG- and GSNO-induced cell apoptosis. Moreover, overexpression of Bcl-2 in NIH3T3 cells can prevent these features of cell death. Furthermore, both MNNG- and GSNO-induced apoptosis of NIH3T3 cells were accompanied with a decrease in the level of glutathione (GSH); whereas Bcl-2 overexpression led to an increase in total cellular glutathione. MNNG was metabolized rapidly to nitric oxide that reacted with glutathione under the catalysis of GSH transferase in NIH3T3 cell to form GSNO. In short, the production of GSNO in cells was found capable of apoptosis initiation while the overexpression of Bcl-2 can prevent MNNG-mediated cell apoptosis through the elevation of glutathione levels.
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PMID:Suppression of N-methyl-N'-nitro-N-nitrosoguanidine- and S-nitrosoglutathione-induced apoptosis by Bcl-2 through inhibiting glutathione-S-transferase pi in NIH3T3 cells. 1059 28

Determinants of differentiation and apoptosis in myelomonocytic leukemia cells (U937) exposed to the novel hybrid polar compound SAHA (suberoylanilide hydroxamic acid) have been examined. In contrast to hexamethylenbisacetamide (HMBA), SAHA-related maturation was limited and accompanied by marked cytoxicity. SAHA-mediated apoptosis occurred within the G0G1 and S phase populations, and was associated with decreased mitochondrial membrane potential, caspase-3 activation, PARP degradation, hypophosphorylation/cleavage of pRB, and down-regulation of c-Myc, c-Myb, and B-Myb. Enforced expression of Bcl-2 or Bcl-XL inhibited SAHA-induced apoptosis, but only modestly potentiated differentiation. While SAHA induced the cyclin-dependent kinase inhibitor p21CIP1, antisense ablation of this CDKI increased, rather than decreased, SAHA-related lethality. In contrast, conditional expression of wild-type p53 failed to modify SAHA actions, but markedly potentiated HMBA-induced apoptosis. Finally, SAHA modestly increased expression/activation of the stress-activated protein kinase (SAPK/JNK); moreover, SAHA-related lethality was partially attenuated by a dominant-negative c-Jun mutant protein (TAM67). SAHA did not stimulate mitogen-activated protein kinase (MAPK), nor was lethality diminished by the specific MEK/MAPK inhibitor PD98059. These findings indicate that SAHA potently induces apoptosis in human leukemia cells via a pathway that is p53-independent but at least partially regulated by Bcl-2/Bcl-XL, p21CIP1, and the c-Jun/AP-1 signaling cascade.
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PMID:Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53. 1059 2

Cisplatin (cis-diamminedichloroplatinum(II), CDDP) is one of the most important chemotherapeutic agents; however, the mechanisms of resistance to this drug are still unknown. Recent reports have demonstrated that chemotherapy can induce apoptosis in some cancer cells, indicating that apoptosis may play a very important role in cancer therapy. Therefore, we used a CDDP-resistant cell line from the human epidermoid carcinoma cell line A431 to investigate whether the modulation of apoptosis influences CDDP resistance. In the CDDP-resistant cell, the cell cycle was not perturbed after CDDP treatment. DNA gel electrophoresis and ELISA of the CDDP-resistant cell showed reduced apoptosis when compared with A431 cells treated with CDDP. We determined the p53, Bcl-2, Bax and CPP32 protein levels by Western blotting. This analysis demonstrated a marked increase in Bcl-2 protein levels and a reduction in CPP32 protein levels in CDDP-resistant cells. Our results indicate that the reduction of apoptosis was one of the CDDP-resistant mechanisms, and that reduced apoptosis in CDDP-resistant cells was influenced by Bcl-2 and CPP32 proteins.
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PMID:Regulation of apoptosis reduction in the cisplatin-resistant A431 cell line by Bcl-2 and CPP32. 1060

The s-Myc is similar to c-Myc in its ability to induce apoptosis requiring caspase activation. However, s-Myc is distinct from c-Myc in that it has activity to suppress tumor growth and does not require wild-type p53 to induce apoptosis. These facts suggest differential regulation between s-Myc and c-Myc. Here we showed that s-Myc-mediated apoptosis triggered by UV was not inhibited by the inactive form mutant JNK (APF), though c-Myc-mediated apoptosis was. Moreover, we found that JNK did not affect the transactivation activity of s-Myc, but stimulated that of c-Myc. In contrast, both Myc-mediated apoptosis and caspase-3-like protease activation were suppressed by kinase-negative MKK6 and an inactive form mutant p38(AGF). Our results indicate that s-Myc does not require the JNK signaling unlike c-Myc during UV-triggered apoptosis, but the MKK6/p38MAPK pathway might regulate common apoptotic machinery for both s-Myc and c-Myc upstream of caspase.
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PMID:Differential role of the JNK and p38 MAPK pathway in c-Myc- and s-Myc-mediated apoptosis. 1062 2

Ataxia-telangiectasia is a hereditary multisystemic disease resulting from mutations of ataxia telangiectasia, mutated (ATM) and is characterized by neurodegeneration, cancer, immune defects, and hypersensitivity to ionizing radiation. The molecular details of ATM function in the nervous system are unclear, although the neurological lesion in ataxia-telangiectasia becomes apparent early in life, suggesting a developmental origin. The central nervous system (CNS) of Atm-null mice shows a pronounced defect in apoptosis induced by genotoxic stress, suggesting ATM functions to eliminate neurons with excessive genomic damage. Here, we report that the death effector Bax is required for a large proportion of Atm-dependent apoptosis in the developing CNS after ionizing radiation (IR). Although many of the same regions of the CNS in both Bax-/- and Atm-/- mice were radioresistant, mice nullizygous for both Bax and Atm showed additional reduction in IR-induced apoptosis in the CNS. Therefore, although the major IR-induced apoptotic pathway in the CNS requires Atm and Bax, a p53-dependent collateral pathway exists that has both Atm- and Bax-independent branches. Further, Atm- and Bax-dependent apoptosis in the CNS also required caspase-3 activation. These data implicate Bax and caspase-3 as death effectors in neurodegenerative pathways.
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PMID:Atm and Bax cooperate in ionizing radiation-induced apoptosis in the central nervous system. 1063 75


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