Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis plays a critical role in the development and homeostasis of tissues, especially those with high cell turnover such as the lymphoid system. We have examined the effects of thyroid hormones, TSH and TRH, on apoptosis of human T lymphocytes. We found that T lymphocytes cultured with T3 and T4, but not TSH nor TRH, in vitro showed enhanced apoptosis, evidenced by DNA ladder formation and characteristic morphological changes. In addition, prolonged cultivation with thyroid hormones of the lymphocytes further enhanced the extent of apoptosis. We also found that treatment with thyroid hormones of T lymphocytes induced reduction of mitochondrial transmembrane potential (delta psi) and production of reactive oxygen species, both of which are intimately associated with apoptotic cell death. In addition, cellular expression of antiapoptotic Bcl-2 protein was clearly reduced by the treatment of lymphocytes with thyroid hormones in vitro. Thus, T lymphocytes treated with thyroid hormones accompany reduction of Bcl-2 protein expression, production of reactive oxygen species, and reduction of mitochondrial delta psi, resulting in apoptotic lymphocyte death. Moreover, we found that lymphocytes in patients with Graves' disease showed enhanced apoptosis compared with those in normal individuals. These results suggest that thyroid hormones have the potential to induce apoptotic cell death of human lymphocytes in vivo and in vitro.
J Clin Endocrinol Metab 1999 Apr
PMID:Effects of thyroid hormones on apoptotic cell death of human lymphocytes. 1019 82

We treated primary epithelial cells from human normal prostate (NEPC) and prostate cancer (CEPC) with all-trans-retinoic acid (RA) to study whether it regulates the activity of tissue transglutaminase (tTGase), an enzyme that accumulates in cells undergoing apoptosis. tTGase activity was assessed by [14C]spermidine incorporation; tTGase, P53, Bcl-2, and p21 protein levels were evaluated by Western blotting; and RA receptors (RAR alpha, -beta, and -gamma), tTGase, retinol-binding protein (RBP), and cellular RBP type I transcripts were determined by semiquantitative RT-PCR. After 72-96 h of 10(-6) mol/L RA treatment, cell growth inhibition and apoptosis were associated with increased tTGase activity in both NEPC and CEPC, and with increased tTGase protein and messenger ribonucleic acid levels only in NEPC. Moreover, RA down-regulated RAR alpha and -beta and increased RBP messenger ribonucleic acid levels in NEPC, whereas it increased RAR beta gene expression and decreased Bcl-2 protein levels in CEPC. Our results suggest that RA induces tTGase gene expression and enzyme activity in normal prostate cells, and that RA-regulated pathways are impaired in cancer cells. Moreover, down-regulation of Bcl-2 protein and up-regulation of RAR beta suggest that retinoid may act on the genetic defect responsible for prostate cancer progression.
J Clin Endocrinol Metab 1999 Apr
PMID:Changes in tissue transglutaminase activity and expression during retinoic acid-induced growth arrest and apoptosis in primary cultures of human epithelial prostate cells. 1019 96

Apoptosis with one regulator, Bcl-2, and proliferation with the marker Ki-67 were studied in 75 endometrial biopsies representing superficial parts of endometrium from 35 regularly menstruating women premenstrually and menstrually. Hormonal withdrawal was studied in serum samples and potentiated in epithelium by the decreasing 17beta-estradiol and progesterone receptor scores 4 days premenstrually. The apoptotic index increased 2 days before the onset of menstruation and peaked on the second menstrual day. The high apoptotic index together with low proliferation in endometrial epithelium at the end of the menstrual cycle are similar to the involution process seen in other hormone-dependent organs. In stroma, the apoptotic index increased later, at the onset of menstruation, and the increase was lower than that in epithelium. The Ki-67 index increased during the last 3 days of the secretory phase, parallel with an increasing progesterone receptor score and decreasing Bcl-2 staining, and peaked at the onset of menstruation. The findings in stroma concur with high proliferation at the end of the menstrual cycle and high cell turnover during menstruation, suggesting the participation of stroma in the renewal process of endometrium.
J Clin Endocrinol Metab 1999 May
PMID:Apoptosis, proliferation, and sex hormone receptors in superficial parts of human endometrium at the end of the secretory phase. 1032 9

In this study, we investigated the expression of Bak, a member of the Bcl-2 protein family, in human polymorphonuclear neutrophils. Northern blot and Western blot analyses revealed that Bak messenger RNA and protein were constitutively expressed in peripheral polymorphonuclear neutrophils and mononuclear cells, as well as in several hematopoietic cell lines. Remarkably, culturing neutrophils for 24 h in the presence or absence of interferon-gamma or tumor necrosis factor-alpha, which have been described to modulate the survival rate of these cells, did not influence the expression of antigenic Bak. Taken together, our data indicate that the expression of the pro-apoptotic protein Bak in polymorphonuclear neutrophils is constitutive, is not subject to modulation, and does not correlate with the neutrophil life span in culture.
Int J Clin Lab Res 1999
PMID:Analysis of the Bak protein expression in human polymorphonuclear neutrophils. 1035 63

In order to determine the mechanism of tumour destruction by tumour-infiltrating lymphocytes (TIL), we examined the ability of both CD4+ and CD8+ effector TIL, and TIL clones, to manifest granzyme-mediated and Fas-mediated destruction of tumour targets. In many in vitro studies TIL have been shown to manifest anti-tumour reactivity, yet many tumours escape immunological destruction. To investigate the role of Fas expression and the concomitant sensitivity to the inducibility of apoptotic death, we derived TIL from four melanomas and one glioma. The glioma, and all but one of the melanomas, expressed Fas, but Fas-mediated apoptosis could only be detected if the targets were treated with cyclohexamide. The melanomas and the glioma all expressed detectable cytoplasmic Bcl-2 protein, known to exert anti-apoptotic activity. Lysis of tumours by CD8-enriched cultures and CD8+ clones was Ca2+-dependent and could not be modified by an anti-Fas MoAb. In CD4-enriched cultures or CD4+ clones with cytotoxic potential against tumour cells, cytotoxicity was also Ca2+-dependent. As Ca2+-dependent cytotoxicity is usually the result of secretion of perforin/granzyme-B, we investigated the presence of perforin in cytotoxic CD4+ clones and demonstrated the presence of granular deposits of this enzyme in some of the CD4+ clones. Although an anti-Fas MoAb did not block the lysis of melanoma targets by CD4+ clones, the examination of Fas-dependent targets demonstrated that these clones also had the potential to kill by the Fas/Fas ligand system. These data suggest that the predominant mechanism in tumour killing by TIL appears to be perforin-granzyme-dependent, and that the solid tumour cell lines we studied are less susceptible to Fas-mediated apoptosis. As non-apoptotic pathways may enhance tumour immunogenicity, exploitation of the perforin-granzyme-dependent cytotoxic T lymphocyte (CTL) pathways may be important for achieving successful anti-tumour responses.
Clin Exp Immunol 1999 Jun
PMID:Studies of the mechanism of cytolysis by tumour-infiltrating lymphocytes. 1036 Dec 24

The cause of neuronal death in Parkinson's, Alzheimer's, and other neurodegenerative diseases is not known, except in some hereditary forms of these disorders in which a mutated gene has been identified. Even in these cases, the molecular mechanisms that underlie the loss of specific populations of neurons have not been determined, although it is highly probable that apoptosis is involved. Some of the biochemical events that occur during apoptosis have been elucidated. We focus in this review on the role played by the proapoptotic caspases, the antiapoptotic proteins of the Bcl-2 family, and the apoptosis associated signal transducers such as ceramide, calcium, and reactive nitrogen or oxygen species. The role of the mitochondria and the possible implication of cell cycle regulators will also be addressed. Of particular interest are the endogenous inhibitory mechanisms and the pharmacologic agents that can be used to block apoptosis signaling cascades, because they offer models for the development of therapeutic strategies designed to prevent the evolution of pathologic neurodegeneration.
Clin Neuropharmacol
PMID:Neuropharmacologic aspects of apoptosis: significance for neurodegenerative diseases. 1036 78

Bcl-2 family proteins are important regulators of apoptosis. To clarify a role of apoptosis and the expression of Bcl-2 family proteins in the pathogenesis of subacute thyroiditis (SAT), we evaluated the expression of Bcl-2, Bax, and Bak by immunohistochemistry and apoptosis by in situ end labeling of fragmented DNA in thyroid tissues from 11 patients with SAT. Apoptotic nuclei were found in granulomas, especially in macrophages/histiocytes and lymphocytes, and in the regenerating follicular cells, but were rarely found in the area of fibrosis. The mean (+/-SD) percentage of apoptotic follicular cells was significantly greater in SAT than that in controls (1.4 +/- 0.8% vs. 0.4 +/- 0.6%). Bcl-2, Bak, and Bax were strongly expressed in the granulomas and regenerating thyroid follicular cells from patients with SAT. Bcl-2 and Bak, but not Bax, were expressed in follicular cells from normal controls. The percentage of apoptotic cells and the expression of Bax in follicular cells did not correlate with age or serum levels of thyroid hormones, C-reactive protein, or thyroglobulin. These data suggest that apoptosis may be involved in the development of SAT and that Bax expression in regenerating thyrocytes may be important for the recovery of SAT.
J Clin Endocrinol Metab 1999 Jun
PMID:Immunohistochemical analysis of Bcl-2, Bax, and Bak expression in thyroid glands from patients with subacute thyroiditis. 1037 34

Vitronectin (VN) is an extracellular matrix (ECM) protein, the synthesis of which in vivo by glioma cells correlates with tumor grade. Although the role of VN as a permissive substrate for glioma migration has been well characterized, its role in conferring a survival advantage for tumor cells has not been addressed previously. By using an in vitro assay of DNA fragmentation as a quantitative measure of apoptotic cell death, we sought to determine whether the sensitivity of two human glioma cell lines (D54 and U251) to drug-induced apoptosis could be inhibited by VN. As well, the extent to which apoptosis could be inhibited was correlated with the levels of the Bcl-2 family of proteins that are known to modulate apoptosis and chemoresistance. Results of the study were: (a) VN coatings, in a dose-dependent manner, inhibited topoisomerase (Topo)-induced apoptosis by up to 50% (optimal coating density, 500 ng/cm2); in contrast, fibronectin (FN), an ECM protein present in abundance in the brain, demonstrated no protection; (b) in a dose-response study, VN clearly conferred a survival advantage (LD50 of Topo: on VN, 120 ng/ml; on FN, 35 ng/ml); (c) the protective effect of VN was not due to enhanced cell adhesion or alterations in the cell cycle distribution; (d) both of the classic integrin receptors that bind VN (alpha(v)beta3, alpha(v)beta5) were capable of mediating this protective effect, because ligation of either of the two classic integrins conferred chemoresistance to Topo; and (e) chemoresistance observed with VN was associated with an increase in expression of two antiapoptotic proteins, Bcl-2 and Bcl-X(L), with a consequent increase in the ratios for Bcl-2:Bax and Bcl-X(L):Bax. VN, an ECM protein preferentially expressed at the tumor-brain interface in vivo, may confer a survival advantage to glioma cells at the advancing tumor margin and may thus, in part, underlie the high level of tumor recurrence at this interface.
Clin Cancer Res 1999 Jun
PMID:Vitronectin, a glioma-derived extracellular matrix protein, protects tumor cells from apoptotic death. 1038 48

Growth effects of tyrphostins A25 and AG1478 on colorectal tumor cells were studied to explore therapeutic potential. Cell number, DNA synthesis and apoptotic index were measured as growth parameters and cell-death-associated proteins Bcl-2 and Bak and protein phosphorylation were analyzed. Both tyrphostins inhibited DNA synthesis and induced apoptosis in tumor cell cultures with different patterns of activity. A25 displayed strong selectivity for the cell lines expressing high levels of epidermal growth factor (EGF), HT29/HI1 and SW480. Inhibition of DNA synthesis was efficient in all cells except T84, and the apoptotic index increased two- to fivefold. By contrast, AG1478 was highly effective in all cell lines. In addition, it caused cell loss in VACO235 adenoma cells at concentrations lower than those necessary to inhibit BrdU incorporation, reflecting preferential retention of cells actively synthesizing DNA. Induction of apoptosis was more efficient with AG1478 than with A25 (tenfold in VACO235). Insulin-like growth factor (IGF1) did not rescue cells exposed to A25 or to high concentrations of AG1478, but was effective with suboptimal amounts of AG1478. Both compounds inhibited phosphorylation of the EGF receptor as well as additional proteins. AG1478 induced expression of Bak and down-regulated Bcl-2. In summary, tyrphostins may provide alternatives for colorectal tumor treatment. Their broader range of activities and the lower susceptibility to interactions with IGF1 can be an advantage over receptor antibodies.
J Cancer Res Clin Oncol 1999 Jul
PMID:Inhibition of epidermal-growth-factor-receptor-dependent signalling by tyrphostins A25 and AG1478 blocks growth and induces apoptosis in colorectal tumor cells in vitro. 1039 57

Cell-matrix adhesion is recognized as a physiologic determinant of cell growth and survival. Integrin occupancy seems to be a primary role. We sought to investigate the signal transduction pathways for integrin effects on cell survival in hepatic stellate cells. Integrin function was antagonized by the soluble integrin recognition sequence pentapeptide Gly-Arg-Gly-Asp-Ser (GRGDS) in primary cultures of rat hepatic stellate cells. Integrin antagonism with GRGDS peptide induced apoptosis. To investigate signal transduction mechanisms for the effect of integrins on cell survival in hepatic stellate cells, the expression of p53, Bcl-2, and Bax was analyzed. Incubation with soluble GRGDS peptide resulted in increased expression of p53 and decreased the Bcl-2/Bax ratio. In conclusion, these findings indicate that the abrogation of cell adhesion with soluble GRGDS peptide plays a critical role in the induction of apoptosis of rat hepatic stellate cells.
J Lab Clin Med 1999 Jul
PMID:Induction of apoptosis in rat hepatic stellate cells by disruption of integrin-mediated cell adhesion. 1040 63


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