Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MLH1 is an integral part of the mismatch repair complex, and the loss of this protein is associated with the acquisition of a mutator phenotype, microsatellite instability, and a predisposition to cancer. Deficiencies in the mismatch repair complex, including the loss of MLH1, result in elevated resistance to specific inducers of DNA damage, yet the mechanisms involved in this DNA-damage resistance are largely unknown. Abnormal cellular responses to DNA damage can lead to the selection of cells with a greater propensity for neoplastic transformation and might also reduce the effectiveness of certain chemotherapeutic drugs. It is therefore important to identify agents that provide selective pressure for growth of MLH1-deficient cells and to characterize further the pathways involved. In this study, we show that both human epithelial and mouse embryo fibroblast cell lines lacking the MLH1 protein are more resistant to two inducers of oxidative stress, hydrogen peroxide and tert-butyl hydroperoxide. Our analyses suggest that the observed differences in cellular viability are mediated primarily through apoptotic pathways and not through deficiencies in cell cycle checkpoint controls. Additional characterization of the signaling pathways for hydrogen peroxide-induced apoptosis in MLH1-proficient cells demonstrates the involvement of increased mitochondrial permeability, the release of cytochrome c, and caspase 3 activation. Together, our data indicate that cells lacking MLH1 may possess a selective growth advantage under oxidatively stressed conditions via the disregulation of apoptosis, possibly involving the mitochondria.
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PMID:Involvement of mammalian MLH1 in the apoptotic response to peroxide-induced oxidative stress. 1124 40

Deregulation of proliferation and apoptosis is known to contribute to neoplastic transformation and growth. Using specific antibodies for the cellular apoptosis susceptibility (CAS) gene, caspase-3, Bcl-2, and Bax, we examined the protein expression in 89 endometrial carcinomas and in 56 samples of nonneoplastic adjacent endometrium for comparison. Immunostaining results were scored with regard to approximate percentage of positive tumor cells (< 10%, 10% to 50%, > 50%) and relative immunostaining intensity (1+, 2+, 3+). In nonneoplastic endometrium, CAS protein was expressed in 70.6%, Bax in 64%, caspase-3 in 52%, and Bcl-2 in 87%. In neoplastic tissue, CAS was present in 93% of the tumors, Bax in 88%, caspase-3 in 77%, and Bcl-2 in 51%. Bcl-2:Bax ratio was > 1 in 9 cases (10%). In cases of atrophy (n = 24) and simple (n = 10) and complex (n = 22) hyperplasia in the adjacent endometrium, lower levels of expression compared with carcinoma were observed for CAS (p = 0.003), caspase-3 (p = 0.034), and Bax (p = 0.04) and higher levels for Bcl-2, although for this protein the results were not statistically significant (p = 0.32). There was no association between immunoscores and FIGO stage. High caspase-3 levels were seen in endometrioid tumor type (p = 0.017). CAS expression was higher in grade 3 tumors (p = 0.002) and older patients (p = 0.013). All tumors of younger patients (< 50 years) were Bcl-2 negative (p = 0.037). Caspase-3 correlated positively with CAS (p = 0.008), Bax (p = 0.04), and low Bcl-2:Bax ratio (p = 0.043), and inversely (as a trend) with Bcl-2 (p = 0.056). Survival analysis (Kaplan-Meier and Cox regression) established a strong association between prognosis and stage, grade, and histologic type (all p < or = 0.0036). In addition, shorter survival was observed for patients whose tumors contained > 50% of positive cells for caspase-3 (p = 0.024) or for CAS (p = 0.04). Age, Bcl-2, Bax, and Bcl-2:Bax ratio did not provide prognostic information. Our results suggest a role of CAS, Bcl-2, Bax, and caspase-3, which are apparently involved in the progressive deregulation of proliferation and apoptosis leading from simple and complex hyperplasia to carcinoma. In addition, CAS and caspase-3 protein levels may be useful markers in predicting the outcome of the patients.
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PMID:Cellular apoptosis susceptibility gene expression in endometrial carcinoma: correlation with Bcl-2, Bax, and caspase-3 expression and outcome. 1160 20

Neural precursor cells (NPCs) populate the embryonic ventricular zone and persist in the subependymal zone of the adult brain. We hypothesized that hereditary and/or acquired mutations in apoptosis-associated genes, such as p53 and caspases, may protect NPCs from DNA damage-induced death and predispose them to subsequent neoplastic transformation. To test this hypothesis, we exposed NPCs from wild-type and targeted gene-disrupted mouse embryos (p53, caspase-9, caspase-3, and bax mutants) to ethyl-nitrosourea (ENU), a known DNA mutagen and neural carcinogen, and measured NPC viability. We found that ENU produced caspase-3 activation and apoptotic NPC death 6-24 h after administration both in vivo and in vitro. This effect was critically dependent on p53 and caspase-9 expression. The long-term effect of intrauterine ENU exposure was examined in control and p53-deficient mice. High grade glial tumors were found in 60% of p53(-/-) young adult mice exposed to ENU on gestational day 12.5 but not in p53(+/-) or p53(+/+) littermates or in untreated p53-deficient mice. All the tumors were located supratentorially and possessed strong immunoreactivity for glial fibrillary acidic protein and the anti-apoptotic molecule Bcl-X(L). These results suggest that intrauterine exposure of NPCs to certain DNA damaging agents may synergistically interact with specific genetic abnormalities (e.g. p53 deficiency) to produce glial neoplasms in the adult brain.
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PMID:Neural precursor cell apoptosis and glial tumorigenesis following transplacental ethyl-nitrosourea exposure. 1178 43

We made use of QNR cells transformed by a thermosensitive (tsNY68) strain of the Rous sarcoma virus (RSV) to compare the effect of p60(v-src) and serum in cultured nerve cells. In this system, both p60(v-src) heat inactivation and serum removal resulted in growth arrest in G1. In both cases, growth arrest was reversible since cell proliferation was rapidly re-induced following respectively p60v-src renaturation or serum re-addition. However, cells did not fully recover their ability to grow in soft agar, suggesting that, in contrast to the cell cycle machinery, the transforming capacities of these cells have been irreversibly altered. We found that p60(v-src) kinase activity prevented detachment from the substratum and cell death following serum removal. Thermal inactivation of p60(v-src) at restrictive temperature (41.5 degrees C), but not serum removal, resulted in dramatic morphological changes, which occurred 4 h after temperature shift up to 41.5 degrees C. Later on, typical features of apoptotic cells could be observed. Cell death was greatly reduced by the caspase-3 inhibitor ZVAD.FMK, but not by the caspase-1 inhibitor Ac-YVAD.CHO. Together, these results suggested that p60(v-src) and serum factors act on distinct pathways, at least in part. In an attempt to identify the signalling pathways involved in the cell response to p60(v-src) down regulation, we found that Erk and Rac were rapidly inactivated following temperature shift up to 41.5 degrees C. Thus, the combined effects of p60(v-src) and serum factors on the cytoskeleton dynamics and the apoptosis machinery are essential for full neoplastic transformation of neuroretina cells.
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PMID:p60(v-src) and serum control cell shape and apoptosis via distinct pathways in quail neuroretina cells. 1185 Aug 37

The transcription factor NF-kappa B is elevated in murine T-cell lymphoma lines compared with normal thymic lymphocytes, and may play a role in the neoplastic transformation of these cells. When T lymphoma cells were treated with the soy isoflavone genistein, a marked reduction in nuclear NF-kappa B levels was detectable predominantly for the p50/p50 homodimer and p50/p65 heterodimer. To examine the mechanism by which NF-kappa B is reduced by genistein, we analyzed the NF-kappa B inhibitor, I kappa B alpha, and detected a 34 kDa cleavage product Delta I kappa B alpha, which was induced by genistein in a dose-dependent manner. Our observation that a pan-caspase inhibitor could inhibit the induction of Delta I kappa B alpha by genistein suggested that caspase activity was responsible for this cleavage product. In support of this idea, we detected an increase in caspase-3 activity in response to increasing time of genistein exposure. When the induction of Delta I kappa B alpha was prevented, we detected no reduction of NF-kappa B levels by genistein. These results support a direct role for Delta I kappa B alpha in the reduction of NF-kappa B by genistein. To determine the effect of genistein on some NF-kappa B target gene products, we examined the antiapoptotic proteins Bcl-2, Bcl-X(L), A1, and cIAP-1. Only changes in A1 and cIAP-1 levels were affected with significant reductions in response to genistein. Generation of the repressive activity of Delta I kappa B alpha on NF-kappa B is a novel mechanism for the reduction of this transcription factor by genistein and the possible effect this may have on the ability of genistein to induce apoptosis in tumor cells.
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PMID:Genistein reduces NF-kappa B in T lymphoma cells via a caspase-mediated cleavage of I kappa B alpha. 1296 87

The involvement of estrogen receptor beta (ERbeta) in prostate carcinogenesis has been hypothesized. Several reports have shown that ERbeta expression was decreased when prostate cells undergo neoplastic transformation, suggesting that it could play a tumor-suppressor role. By restoring ERbeta expression in prostatic carcinoma cells by adenoviral delivery, we aimed to test this hypothesis. We observed that ERbeta strongly inhibited the invasiveness and the growth of these cells. In addition, ERbeta cells were undergoing apoptosis, as shown by quantification of Bax, poly(ADP-ribose) polymerase and caspase-3 expression. Our data suggest that ERbeta acts as a tumor-suppressor by its anti-proliferative, anti-invasive and pro-apoptotic properties.
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PMID:Expression of estrogen receptor beta in prostate carcinoma cells inhibits invasion and proliferation and triggers apoptosis. 1514 89

The phytochemical composition of passionfruit juice (PFJ) was hypothesized to have valuable anti-cancer activity, and this was tested in a BALB/c 3T3 neoplastic transformation model. A higher concentration of PFJ compared with a lower concentration was effective in reducing the number, size, and invasiveness of transformed foci. When incubated with another mammalian cell line, the MOLT-4, PFJ was unable to alter the cell cycle kinetics while at the same time was successful in inducing the activity of caspase-3, an enzyme that commits the cell to apoptosis. This suggests that phytochemicals found in PFJ were able to produce the changes in transformed foci due to apoptotic mechanisms rather than by a reduction in cell proliferation. These beneficial results were achieved at levels that could theoretically be attained in the plasma after consumption of the juice.
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PMID:Inhibition of neoplastic transformation of benzo[alpha]pyrene-treated BALB/c 3T3 murine cells by a phytochemical extract of passionfruit juice. 1567 81

Under normal conditions, in human endometrium, apoptotic and antiapoptotic factors play an important role in tissue homeostasis. Abnormalities of apoptosis, a process implicated in several events in the reproductive organs, may contribute to neoplastic transformation. The present study aimed to investigate the involvement of both the receptorial and the mitochondrial pathways of apoptosis in normal endometrium and in endometrial carcinoma, by measuring caspase-3 and caspase-8 activities and cytosolic cytochrome c levels. Twelve endometrial carcinomas and nine normal endometrial specimens (four in mild proliferative phase, five in late secretory phase) were included in this study. Cytosolic fractions, obtained by differential centrifugation of tissue homogenates, were analyzed for caspase-3 and caspase-8 activities, as well as for cytochrome c content. Caspase-8 activity in normal secretory phase endometrium was higher than that in the proliferative phase and in the endometrial carcinoma. Moreover, higher cytochrome c levels were detected in endometrial carcinoma with respect to normal secretive endometrium. No significant differences were found in caspase-3 activity between normal and pathologic endometrium. The results obtained suggest that in normal endometrium, apoptosis takes place through the activation of both receptorial and mitochondrial pathways. Defects in both these pathways may contribute to the development of endometrial carcinoma.
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PMID:Receptorial and mitochondrial apoptotic pathways in normal and neoplastic human endometrium. 1588 80

Poly(ADP-ribose)polymerase (PARP-1), a nuclear enzyme activated by DNA strand breaks, is involved in DNA repair, aging, inflammation, and neoplastic transformation. In diabetes, reactive oxygen and nitrogen species occurring in response to hyperglycemia cause DNA damages and PARP-1 activation. Because circulating mononuclear cells (MNCs) are involved in inflammation mechanisms, these cells were chosen as the experimental model to evaluate PARP-1 levels and activity in patients with type 2 diabetes. MNCs were isolated from 25 diabetic patients (18 M, 7 F, age, 63.5 +/- 10.2 years, disease duration 17.7 +/- 8.2 years) and 11 age and sex matched healthy controls. PARP-1 expression and activity were analyzed by semi-quantitative PCR, Western and activity blot, and immunofluorescence microscopy. PARP-1-mRNA expression was increased in MNCs from all diabetic patients versus controls (P < 0.01), whereas PARP-1 content and activity were significantly lower in diabetic patients (P < 0.0001). To verify whether low PARP-1 levels and activity were due to a proteolytic effect of caspase-3 like, the latter activation was measured by a fluorimetric assay. Caspase-3 activity in MNCs was significantly higher in diabetic patients versus control subjects (P < 0.0001). The different PARP-1 behavior in MNCs from patients with type 2 diabetes could therefore be responsible for the abnormal inflammation and infection responses in diabetes.
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PMID:Poly(ADP-ribose)polymerase activity is reduced in circulating mononuclear cells from type 2 diabetic patients. 1589 95

Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN or CD147), a member of the immunoglobulin family and a glycoprotein enriched on the surface of tumor cells, promotes invasion, metastasis, and growth and survival of malignant cells and confers resistance to some chemotherapeutic drugs. However, the molecular mechanisms underlying the actions of EMMPRIN are not fully understood. In this study we sought to determine whether EMMPRIN contributes to the malignant phenotype of breast cancer by inhibiting anoikis, a form of apoptosis induced by loss or alteration of cell-cell or cell-matrix anchorage, and to explore the signaling pathways involved. We found that in the absence of attachment, human breast carcinoma cells expressing high levels of EMMPRIN formed less compact aggregates with larger surface area and less fibronectin matrix assembly, had higher viability, and were resistant to anoikis. Knockdown of EMMPRIN expression by RNA interference (small interfering RNA or short hairpin RNA) sensitized cancer cells to anoikis, as demonstrated by activation of caspase-3, increased DNA fragmentation, and decreased cellular viability. Furthermore, we observed that the accumulation of Bim, a proapoptotic BH3-only protein, was reduced in EMMPRIN-expressing cells and that silencing of EMMPRIN expression elevated Bim protein levels and enhanced cellular sensitivity to anoikis. Treatment of cells with a MEK inhibitor (U0126) or proteasome inhibitor (epoxomicin) also up-regulated Bim accumulation and rendered cells more sensitive to anoikis. These results indicated that expression of EMMPRIN protects cancer cells from anoikis and that this effect is mediated at least in part by a MAP kinase-dependent reduction of Bim. Because anoikis deficiency is a key feature of neoplastic transformation and invasive growth of epithelial cancer cells, our study on the role of EMMPRIN in anoikis resistance and the mechanism involved underscores the potential of EMMPRIN expression as a prognostic marker and novel target for cancer therapy.
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PMID:Extracellular matrix metalloproteinase inducer (CD147) confers resistance of breast cancer cells to Anoikis through inhibition of Bim. 1644 28


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