Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

c-Myc promotes apoptosis by destabilizing mitochondrial integrity, leading to the release of proapoptotic effectors including holocytochrome c. Candidate mediators of c-Myc in this process are the proapoptotic members of the Bcl-2 family. We show here that fibroblasts lacking Bak remain susceptible to c-Myc-induced apoptosis whereas bax-deficient fibroblasts are resistant. However, despite this requirement for Bax, c-Myc activation exerts no detectable effects on Bax expression, localization, or conformation. Moreover, susceptibility to c-Myc-induced apoptosis can be restored in bax-deficient cells by ectopic expression of Bax or by microinjection of a peptide comprising a minimal BH3 domain. Microinjection of BH3 peptide also restores sensitivity to c-Myc-induced apoptosis in p53-deficient primary fibroblasts that are otherwise resistant. By contrast, there is no synergy between BH3 peptide and c-Myc in fibroblasts deficient in both Bax and Bak. We conclude that c-Myc triggers a proapoptotic mitochondrial destabilizing activity that cooperates with proapoptotic members of the Bcl-2 family.
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PMID:c-Myc functionally cooperates with Bax to induce apoptosis. 1216 10

The role of Bax and Bak, 2 proapoptotic proteins of the Bcl-2 family, was analyzed in primary B-cell chronic lymphocytic leukemia (CLL) cells following in vitro treatment with fludarabine, dexamethasone, or the combination of fludarabine with cyclophosphamide and mitoxantrone (FCM). A strong correlation was found between the number of apoptotic cells and the percentage of cells stained with antibodies recognizing conformational changes of Bax (n = 33; r = 0.836; P <.001) or Bak (n = 10; r = 0.948; P <.001). Preincubation of CLL cells with Z-VAD.fmk (N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone), a broad caspase inhibitor, abolished caspase-3 activation, exposure of phosphatidylserine residues, and reactive oxygen species generation; partially reversed the loss of transmembrane mitochondrial potential (DeltaPsim); but did not affect Bax or Bak conformational changes. These results indicate that the conformational changes of Bax and Bak occur upstream of caspase activation or are caspase independent. Following drug-induced apoptosis, Bax integrates into mitochondria, as demonstrated by fluorescence microscopy and Western blot, without changes in the total amount of Bax or Bak protein. Fludarabine and FCM induce p53 stabilization, but do not seem to be essential in inducing Bax and Bak conformational changes, as they are also observed in dexamethasone-treated CLL cells. These results demonstrate that, in CLL cells, the change in the intracellular localization of Bax from cytosol to mitochondria and the conformational changes of Bax and Bak are among the early steps in the induction of cell death.
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PMID:Spontaneous and drug-induced apoptosis is mediated by conformational changes of Bax and Bak in B-cell chronic lymphocytic leukemia. 1217 4

BAG-1 protein can be expressed as four isoforms of 50, 46, 33 and 29 kDa with different subcellular localizations, which may have different functions in anti-apoptosis, but the exact mechanism remains unclear. We constructed BAG-1 full length and deletion mutated plasmids in a pCR3.1 vector and established stable transfections of BAG-1 isoforms in low BAG-1 expressing C33A cells. Treatment of the transfected cells with cisplatin, staurosporine, paclitaxel and doxorubicine showed that BAG-1 p50, p46 and p33 isoforms enhanced the resistance to apoptosis. BAG-1 p50, p46 and p33 exhibited different degrees of apoptosis inhibition in the transfected cells and BAG-1 p46 isoform had the most pronounced effect on anti-apoptosis. BAG-1 p29 failed to protect the transfected cells from apoptosis. Resistance to apoptosis by BAG-1 isoforms was correlated with decreased caspase-3 activation. We also detected the expression of Bax, Bak, p53, Bcl-2, Bcl-X(L), AIF and MRP1 by Western blots. Bcl-2 protein expression was significantly increased in p50, p46 and p33 transfected cells, while the expression of Bax, Bak, p53, Bcl-X(L) and MRP1 was essentially unchanged. These in vitro results suggest that distinct isoforms of BAG-1 have different anti-apoptotic functions and their functions may be correlated to increased Bcl-2 expression.
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PMID:Distinct BAG-1 isoforms have different anti-apoptotic functions in BAG-1-transfected C33A human cervical carcinoma cell line. 1237 Aug 27

Cryotherapy, a method of in situ ablation, is used in the treatment of colorectal liver metastases with variable results. During the treatment, the central area of treated tumor undergoes necrotic destruction by lethal cryo-injury; however, the cellular response of tumor exposed to sublethal cryo-injury at the peripheral zone is unclear. In our study, we have identified the induction of apoptosis by cryo-injury at -10 degrees C in 4 colorectal cancer cell lines (HT29, HCT116, KM12C and KM12SM). The apoptosis was characterized by chromatin condensation, transferase-mediated dUTP nick end-labeling (TUNEL) staining, proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) and cytokeratin 18, and activation of caspase-3. The occurrence and intensity of cryo-induced apoptosis did not correlate with the functional status of p53 in the cell lines studied. The expression of anti-apoptotic proteins (Bcl-2, Bcl-X(L)) and pro-apoptotic proteins (Bax, Bcl-X(S), Bad, and Bak) in response to cryo-injury varied in this cell line panel. The basal level of Bcl-2/Bax protein ratio correlated inversely to the apoptotic rate. We further demonstrated that Bax level decreased in cytosol and increased in mitochondria, followed by a loss of mitochondrial membrane potential after cryo-injury in HT29 cells. These findings indicate that cryo-injury induces apoptosis in colorectal cancer cells via disruption of mitochondrial integrity. The cryo-induced apoptosis was also identified in a nude mouse tumor xenograft model. Our elucidation of the apoptosis pathway induced by cryo-injury implies that synergistic combination of cryosurgery with pharmacological agents that augment of apoptosis induction may have clinical relevance in treating colorectal liver metastasis.
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PMID:Apoptosis induced by cryo-injury in human colorectal cancer cells is associated with mitochondrial dysfunction. 1247 19

Bak is a pro-apoptotic member of the Bcl-2 family of genes that are involved in regulation of programmed cell death. By means of immunohistochemical methods, Bak expression was evaluated in formalin-fixed, paraffin-embedded diagnostic specimens from 83 patients with T1-T4 oral tongue squamous cell carcinomas (SCC). The fractions of tumor cells expressed Bak and their staining intensities were given an expression score. Bak expression was compared with our previous investigated apoptosis-related parameters such as apoptotic index (AI), Bax and Bcl-2 expression, and p53 accumulation. Bak expression correlated positively with Bcl-2 expression (p=0.0001). No significant correlation was found between Bak expression and Bax expression, AI, or p53 accumulation. Patients with Bak expression exceeding the mean value had poorer disease-specific survival when compared with those with values below the mean Bak expression (p=0.01). Cox proportional hazards regression analysis revealed that Bak expression was a significant, independent prognostic variable (p=0.0325). A two-parameter combination of Bak expression and Bax expression, AI, or p53 accumulation revealed an enhanced prognostic potential (p<0.0001) when compared with single parameters. We conclude that Bak expression, particularly in combination with Bax expression, as well as in combination with AI, or p53 accumulation, has prognostic value in tongue SCC.
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PMID:Prognostic value of Bak expression in oral tongue squamous cell carcinomas. 1257 74

The mechanisms of injury- and disease-associated apoptosis of neurons within the CNS are not understood. We used a model of cortical injury in rat and mouse to induce retrograde neuronal apoptosis in thalamus. In this animal model, unilateral ablation of the occipital cortex induces apoptosis of corticopetal projection neurons in the dorsal lateral geniculate nucleus (LGN), by 7 days post-lesion, that is p53 modulated and Bax dependent. We tested the hypothesis that this degenerative process is initiated by oxidative stress and early formation of DNA damage and is accompanied by changes in the levels of pro-apoptotic mediators of cell death. Immunoblotting revealed that the protein profiles of Bax, Bak and Bad were different during the progression of neuronal apoptosis in the LGN. Bax underwent a subcellular redistribution by 1 day post-lesion, while Bak increased later. Bad showed an early sustained increase. Cleaved caspase-3 was elevated maximally at 5 and 6 days. Active caspase-3 underwent a subcellular translocation to the nucleus. A dramatic phosphorylation of p53 was detected at 4 days post-lesion. DNA damage was assessed immunocytochemically as hydroxyl radical adducts (8-hydroxy-2-deoxyguanosine) and single-stranded DNA. Both forms of DNA damage accumulated early in target-deprived LGN neurons. Transgenic overexpression of superoxide dismutase-1 provided significant protection against the apoptosis but antioxidant pharmacotreatments with trolox and ascorbate were ineffective. We conclude that overlapping and sequential signaling pathways are involved in the apoptosis of adult brain neurons and that DNA damage generated by superoxide derivatives is an upstream mechanism for p53-regulated, Bax-dependent apoptosis of target-deprived neurons.
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PMID:Early events of target deprivation/axotomy-induced neuronal apoptosis in vivo: oxidative stress, DNA damage, p53 phosphorylation and subcellular redistribution of death proteins. 1264 45

There is increasing evidence that some neuronal death after brain ischaemia is mediated by the action of cysteine-requiring aspartate-directed proteases (caspases), the proteases responsible for apoptosis in mammals, although this form of neuronal death is not always accompanied by the morphological changes that are typical of apoptosis in other tissues. Caspase-mediated neuronal death is more extensive after transient than permanent focal brain ischaemia and may contribute to delayed loss of neurons from the penumbral region of infarcts. The activation of caspases after brain ischaemia is largely consequent on the translocation of Bax, Bak, and other BH3-only members of the Bcl-2 family to the mitochondrial outer membrane and the release of cytochrome c, procaspase-9, and apoptosis activating factor-1 (Apaf-1) from the mitochondrial intermembrane space. How exactly ischaemia induces this translocation is still poorly understood. NF-kappaB, the c-jun N-terminal kinase-c-Jun pathway, p53, E2F1, and other transcription factors are probably all involved in regulating the expression of BH3-only proteins after brain ischaemia, and mitochondrial translocation of Bad from sequestering cytosolic proteins is promoted by inactivation of the serine-threonine kinase, Akt. Other processes that are probably involved in the activation of caspases after brain ischaemia include the mitochondrial release of the second mitochondrial activator of caspases (Smac) or direct inhibitor-of-apoptosis-binding protein with low pI (DIABLO), the accumulation of products of lipid peroxidation, a marked reduction in protein synthesis, and the aberrant reentry of neurons into the cell cycle. Non-caspase-mediated neuronal apoptosis may also occur, but there is little evidence to date that this makes a significant contribution to brain damage after ischaemia. The intracellular processes that contribute to caspase-mediated neuronal death after ischaemia are all potential targets for therapy. However, anti-apoptotic interventions in stroke patients will require detailed evaluation using a range of outcome measures, as some such interventions seem simply to delay neuronal death and others to preserve neurons but not neuronal function.
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PMID:Apoptosis and brain ischaemia. 1265 66

We have previously reported that in tumorigenic pancreatic beta-cells, calcitriol exerts a potent antitumorigenic effect by inducing apoptosis, cell growth inhibition, and reduction of solid beta-cell tumors. Here we have studied the molecular pathways involved in the antineoplastic activity of calcitriol on mouse insulinoma beta TC(3) cells, mouse insulinoma beta TC expressing or not expressing the oncogene p53, and beta TC-tet cells overexpressing or not the antiapoptotic gene Bcl2. Our results indicate that calcitriol-induced apoptosis was dependent on the function of p53 and was associated with a biphasic increase in protein levels of transcription factor nuclear factor-kappa B. Calcitriol decreased cell viability by about 40% in p53-retaining beta TC and in beta TC(3) cells; in contrast, beta TC p53(-/-) cells were only minimally affected. Calcitriol-induced cell death was regulated by members of the Bcl-2 family of apoptosis regulatory proteins, as shown by calcitriol-induced up-regulation of proapoptotic Bax and Bak and the lack of calcitriol-induced cytotoxicity in Bcl-2-overexpressing insulinoma cells. Moreover, calcitriol-mediated arrest of beta TC(3) cells in the G(1) phase of the cell cycle was associated with the abnormal expression of p21 and G(2)/M-specific cyclin B2 genes and involved the DNA damage-inducible factor GADD45. Finally, in beta TC(3) cells, calcitriol modulated the expression of IGF-I and IGF-II genes. In conclusion, these findings contribute to the understanding of the antitumorigenic effects of calcitriol on tumorigenic pancreatic beta-cells and further support the rationale of its utilization in the treatment of patients with malignant insulinomas.
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PMID:Molecular pathways involved in the antineoplastic effects of calcitriol on insulinoma cells. 1269 89

Apoptosis has received widespread attention for its essential roles in biology, medicine and cancer. We previously found that normal, human papillomavirus (HPV) 16-immortalized and their transformed endocervical cells were increasingly resistant to apoptosis induced by a cancer therapeutic drug. Here, analogously, another common anticancer drug, 5-fluorouracil, in an ectocervical cell carcinogenesis model induced apoptosis in primary human ectocervical cells (HEC), whereas HPV18-immortalized HEC (HEC-18) and transformed HEC-18 (HEC-18T) were more resistant. Growth in serum/low density lipoprotein (LDL)-containing medium reversed resistance to 5-fluorouracil-induced apoptosis, particularly in HEC-18T. Cell viability results confirmed these findings. Using Western blots to compare protein levels with those of HEC not treated with 5-fluorouracil, the fold changes in HEC-18 and HEC-18T in LDL-free medium were 1.6-6.1-fold lower for pro-apoptotic p53, Bak and Bax. Four anti-apoptotic proteins were altered -2.1 to+14.6-fold for Bcl-2 and BAG-1 isoform p33 and p29. For BAG-1 p50 and p46, HEC-18 were weakly expressed and HEC-18T were moderately higher. Grown in LDL-containing medium, the differences in pro-apoptotic protein levels were mostly reversed. Expression was 1.4-32-fold higher in HEC-18 and HEC-18T of p53, Bax, BAG-1 p29, BAG-1 p33 and total BAG-1. These results showed that HEC carcinogenesis results in resistance to 5-fluorouracil-induced apoptosis, associated with reduced expression during carcinogenesis of pro-apoptotic proteins and increased expression of specific anti-apoptotic proteins.
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PMID:Apoptosis, 5-fluorouracil sensitivity and expression of apoptotic proteins in a human ectocervical cell carcinogenesis model using different media. 1270 50

Thymidylate synthase (TS) is a chemotherapeutic target for the fluoropyrimidine 5-fluorouracil (5-FU) and antifolate tomudex (TDX). Using the MCF-7 breast cancer line, we have developed a cell line with inducible TS expression termed M7TS90. Inducible TS expression in this line resulted in a moderate (approximately 3-fold) increase in 5-FU 50% inhibitory concentration at 72 hours (IC-50(72 h)) dose and a dramatic (approximately 24-fold) increase in the IC-50(72 h) dose of TDX, but did not affect chemosensitivity to cisplatin, oxaliplatin, irinotecan, and paclitaxel. In the absence of drug treatment, inducible TS expression had no effect on expression of the p53 tumor suppressor gene. However, TS induction abrogated p53, p21, Fas, and Bak induction in response to TDX, but not 5-FU. Similarly, downregulation of Bcl-2 was reversed by inducible TS expression in TDX, but not 5-FU-treated cells. Our results indicate that inducible TS expression in M7TS90 cells modulates p53 and p53 target gene expression in response to TDX, but not 5-FU.
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PMID:The interaction of thymidylate synthase expression with p53-regulated signaling pathways in tumor cells. 1280 89


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