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)

Bcl-2 and Bax proteins, which are involved in repressing and promoting programmed cell death, respectively, have been investigated immunohistochemically and by Western blot analysis in a series of thyroid tumours. Three immunostaining patterns were identified. Benign lesions and well-differentiated thyroid carcinomas displayed a profile similar to that of normal follicular epithelium, in which Bcl-2 immunostaining was predominant. Thyroid carcinomas associated with an aggressive behaviour, such as the tall-cell variant of papillary carcinoma and the poorly differentiated carcinomas, co-expressed both proteins. Finally, anaplastic carcinomas expressed only the Bax protein. Western blot analyses revealed that the anti-Bcl-2 antibody recognized two bands, of molecular weights 21 kDa and 25 kDa. This was only seen in the tall-cell papillary carcinomas and in the anaplastic carcinomas.
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PMID:Bcl-2 and Bax expression in thyroid tumours. An immunohistochemical and western blot analysis. 908 15

The expression of two autoimmune thyroid diseases. GD and idiopathic myxoedema, is associated with antibodies to the thyroid-stimulating hormone (TSH) receptor. Thyroid stimulating antibodies (TSAb) in GD are TSH agonists and cause hyperthyroidism as well as goitre, whereas thyroid stimulation blocking antibodies (TSBAb) in idiopathic myxoedema are TSH antagonists and cause hypothyroidism and thyroid atrophy. We investigated the effect of antibodies to TSH receptor on Fas-mediated apoptosis of thyroid epithelial cells (thyrocytes). Human IgG was isolated from healthy donors, patients with GD and idiopathic myxoedema. Human thyrocytes were obtained from surgical specimens. Thyrocytes were cultured in the presence or absence of human IgG with or without interferon-gamma (IFN-gamma) or IL-1beta for a specified time. After incubation, we examined the level of cAMP in cultured supernatants and both Fas and Bcl-2 expression on thyrocytes. In addition, we examined anti-Fas-mediated apoptosis of thyrocytes. Fas expression on thyrocytes was significantly down-regulated by Graves' IgG and TSH, although idiopathic myxoedema IgG did not affect Fas expression on thyrocytes. Idiopathic myxoedema IgG abrogated the effect of TSH on both cAMP production and inhibition of Fas expression on thyrocytes. Treatment of thyrocytes with IL-1beta or IFN-gamma caused a marked augmentation of Fas expression on thyrocytes. The increase of Fas expression of thyrocytes induced by IL-1beta or IFN-gamma was significantly suppressed in the presence of TSH or Graves' IgG. Anti-Fas-induced apoptosis of thyrocytes was observed in thyrocytes treated with IL-1beta or IFN-gamma, but was markedly inhibited in the presence of TSH or Graves' IgG. Furthermore, idiopathic myxoedema IgG abrogated most of the inhibitory effect of TSH on Fas-mediated apoptosis of thyrocytes treated with IL-1beta or IFN-gamma. Bcl-2 expression of thyrocytes did not change after stimulation with TSH, Graves' IgG, idiopathic myxoedema IgG, IL-1beta or IFN-gamma. These results suggest that TSAb found in Graves' patients may be potentially involved in the development of goitre by inhibition of Fas-mediated apoptosis of thyrocytes. In addition, TSBAb inhibit the action of TSH and increase the sensitivity toward Fas-mediated apoptosis of thyrocytes, inducing thyroid atrophy seen in patients with idiopathic myxoedema.
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PMID:Modulation of Fas-mediated apoptosis of human thyroid epithelial cells by IgG from patients with Graves' disease (GD) and idiopathic myxoedema. 940 48

In order to investigate the possible involvement of apoptosis in the pathogenesis of thyroid-associated ophthalmopathy (TAO), we studied the expression of Fas, Fas ligand (FasL), and Bcl-2 in extraocular muscle tissues from patients with TAO by immunohistochemistry using monoclonal antibodies against Fas, FasL, and Bcl-2. Apoptosis was detected by in situ end-labeling of fragmented DNA. Apoptosis was detected in extraocular muscle tissues from 17 of 19 patients with TAO and, to a smaller degree in 4 of 7 normal control subjects. The mean percentages of apoptotic nuclei were 12.1% in TAO eye muscle fibers and 16.4% in TAO interstitial cells, compared with 2.2% and 0.4% in normal eye muscle fibers and interstitial cells, respectively. The percentage of apoptotic nuclei in eye muscle fibers correlated with the enlargement of eye muscle tissue (r = 0.47, p < 0.05). Fas was demonstrated on the surfaces of extraocular muscle fibers in 11 of 18 patients with TAO, but not in normal extraocular muscle tissues. Neither TAO nor normal extraocular muscle tissues expressed Bcl-2. FasL was detected in infiltrating mononuclear cells in extraocular muscle tissue from a patient with TAO. These data suggest that Fas-mediated apoptosis may occur in extraocular muscle tissue from patients with TAO and may be involved in the late stage of TAO.
Thyroid 1998 Apr
PMID:Possible involvement of Fas-mediated apoptosis in eye muscle tissue from patients with thyroid-associated ophthalmopathy. 958 96

Hashimoto's thyroiditis (HT) is an autoimmune disorder characterized by diffuse thyroid lymphocytic infiltration and follicle destruction. Cross-linking of the Fas receptor with its own ligand (FasL) triggers apoptosis in various systems, whereas the Bcl-2 protooncogene inhibits apoptotic cell death. The involvement of Fas, FasL, and Bcl-2 in the apoptotic process in HT was evaluated in 15 thyroid tissue samples from patients with HT stained for apoptosis and for Fas, FasL, and Bcl-2 protein expression. Eight samples from healthy thyroid tissue were used for comparison. Thyroid follicles in HT samples exhibited strong staining for Fas and FasL and a high percentage of apoptosis (30.3 +/- 14.5%, mean +/- SD), in contrast to normal control follicles that exhibited moderate Fas, minimal or no FasL, and hardly any apoptosis. Immunostaining for Bcl-2 was high in normal, and weak in involved, thyroid follicles. Infiltrating lymphocytes stained weakly for FasL and strongly for Bcl-2. We conclude that follicular cells in HT undergo apoptosis by concomitant up-regulation of FasL and Fas and down-regulation of Bcl-2 protein. The lymphocytes do not seem to be directly engaged in the process with their own FasL, but they may provide the appropriate cytokine milieu that, in turn, up-regulates Fas and/or FasL leading to apoptosis.
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PMID:Fas/Fas ligand up-regulation and Bcl-2 down-regulation may be significant in the pathogenesis of Hashimoto's thyroiditis. 962 60

Thyroid toxicity of iodide excess has been demonstrated in animals fed with an iodide-rich diet; in vitro iodide is cytotoxic, inhibits cell growth, and induces morphological changes in thyroid cells of some species. In this study, we investigated the effect of iodide excess in an immortalized thyroid cell line (TAD-2) in primary cultures of human thyroid cells and in cells of nonthyroid origin. Iodide displayed a dose-dependent cytotoxicity in both TAD-2 and primary thyroid cells, although at different concentrations, whereas it had no effect on cells of nonthyroid origin. Thyroid cells treated with iodide excess underwent apoptosis, as evidenced by morphological changes, plasma membrane phosphatidylserine exposure, and DNA fragmentation. Apoptosis was unaffected by protein synthesis inhibition, whereas inhibition of peroxidase enzymatic activity by propylthiouracil completely blocked iodide cytotoxicity. During KI treatment, reactive oxygen species were produced, and lipid peroxide levels increased markedly. Inhibition of endogenous p53 activity did not affect the sensitivity of TAD-2 cells to iodide, and Western blot analysis demonstrated that p53, Bcl-2, Bcl-XL, and Bax protein expression did not change when cells were treated with iodide. These data indicate that excess molecular iodide, generated by oxidation of ionic iodine by endogenous peroxidases, induces apoptosis in thyroid cells through a mechanism involving generation of free radicals. This type of apoptosis is p53 independent, does not require protein synthesis, and is not induced by modulation of Bcl-2, Bcl-XL, or Bax protein expression.
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PMID:Iodide excess induces apoptosis in thyroid cells through a p53-independent mechanism involving oxidative stress. 1065 Sep 40

Goitrogenesis is accompanied by hyperplasia and hypertrophy and involves tissue remodelling and angiogenesis. During the involution of the goitre there must be removal of this increased thyroid volume, in addition to further remodelling, which may involve apoptosis. We investigated apoptosis in the involuting rat thyroid using male Fisher rats that were on a goitrogenic regimen for 14 days and then returned to a normal diet. Thyroid weights increased fourfold with the goitrogenic regimen. During involution, the largest decrease in weight was between day 2 and day 4 after withdrawal of treatment. After 34 days of involution, the thyroid weight plateaued, but had not returned to control values. High levels of Bcl-2 immunoreactivity were observed in normal and goitrous rat thyroids. These high levels were significantly reduced at 2 days of involution, after which high levels of Bcl-2 immunoreactivity returned. In situ end-labelling of apoptotic cells showed that there was an increase in the number of cells undergoing DNA fragmentation during goitrogenesis (1.0+/-0.8 cells/100 cells, n=9) compared with controls, in which no positive staining was observed. After 2 days of goitrogen withdrawal, there was a further fourfold increase in the number of in situ end-labelled cells (day 16: 4.1+/-1.7, n=9). Numbers of positive cells returned to low levels after 4 days of involution (day 18: 0.3+/-0.8, n=9). Using antiserum to apoptosis-specific protein, we found increased immunoreactivity during goitrogenesis and after 2 days of involution that was localised predominantly with the stromal and vascular tissue at both time points. The data show that rapid downregulation of Bcl-2 accompanies thyroid involution, which involves increased levels of apoptosis within the stromal compartment.
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PMID:Apoptosis during goitre involution - the role of Bcl-2. 1069 72

Apoptosis is a highly regulated mechanism of cell death involved in normal development, immune regulation, and homeostasis. Abnormal apoptotic activity has been implicated in a variety of diseases including cancer, autoimmunity, and degenerative disorders. In the thyroid, altered cell death may play a role in the pathogenesis of autoimmune disorders such as Hashimoto's thyroiditis and Graves' disease. Apoptosis-signaling pathways can be initiated through activation of death receptors or in response to cellular damage, such as in gamma irradiation. It has been demonstrated that Fas, tumor necrosis factor, and tumor necrosis factor-related apoptosis-inducing ligand pathways are present and functional in the thyroid, although the expression of these molecules and their roles in thyroid autoimmunity have been debated. Thyroid apoptosis is regulated at multiple levels, including receptor and ligand expression, and the expression of antiapoptotic proteins, such as FAP-1 and Bcl-2. These factors may provide potential mechanisms for modifying the pathogenesis of autoimmune thyroid disease.
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PMID:Thyroid cell apoptosis. A new understanding of thyroid autoimmunity. 1087 35

Programmed cell death or apoptosis is central both in physiology during development and in disease. The mechanism of apoptosis is under the control of antiapoptotic survival genes of the Bcl-2 family and proapoptotic death receptors of the TNF superfamily (Fas, TNFR, TRAILR). Following death signal, the death receptor binds to its own receptor and initiates, through binding of adaptors, a cascade of events mediated by the autoproteolytic activation of specific enzymes called caspases. This enzyme activation is ultimately responsible for the dissembly of basic nuclear and cytoplasmic cell structures leading to cell death. In certain cell systems, antiapoptotic genes of the Bcl-2 family prevent the proapoptotic pathway. One of their roles is to maintain mitochondrial function integrity. In autoimmune destructive thyroiditis high levels of apoptosis have been demonstrated particularly within the destructed follicles near the infiltrated areas in comparison to Graves' disease and non autoimmune glands. In Hashimoto's thyroiditis Fas expression has been found increased on thyrocytes and in vitro can be modulated by proinflammatory cytokines. FasL expression on thyrocytes remains controversial. Thyroid cells from Graves' disease and multinodular glands are known to kill Fas expressing target cells although Hashimoto's thyrocytes are not efficient effector cells. Intrathyroidal lymphocytes from Hashimoto's thyroids maintain functional killer activity. These findings would suggest that intrathyroidal lymphocytes could be responsible for thyrocyte death in vivo. Whether this mechanism is Fas/FasL, TRAIL/TRAILR dependent can not be confirmed as specific blocking reagents were not able to inhibit cell induced death. In Hashimoto's thyroiditis an impairment of Bcl-2 and Bcl-X anitapoptotic genes on thyrocytes has also been detected. Bcl-X expression can be down-regulated in vitro by incubation with cytokines. These findings suggest that thyrocyte death may not exclusively be the result of specific interactions between death receptor and their ligands but it may involve simultaneous impairment of protective genes of the Bcl-2 family. Whether the impairment of the Bcl-2 family is a direct consequence of environmental stimuli or is the result of an intrinsic thyrocyte (mitochondrial?) alteration is as yet not known.
Thyroid 2000 Jul
PMID:Death of the autoimmune thyrocyte: is it pushed or does it jump? 1144 11

Several mechanisms are probably involved in determining the evolution of autoimmune thyroid disease (AITD) towards either hypothyroidism and the clinical syndrome known as Hashimoto's thyroiditis (HT) or toward hyperthyroidism and the symptoms of Graves' disease (GD). To gain further insight into such mechanisms we performed an exhaustive comparative analysis of the expression of key molecules regulating cell death (Fas, Fas ligand [FasL], Bcl-2) and apoptosis in both thyrocytes and thyroid infiltrating lymphocytes (TILs) from patients with either GD or HT. GD thyrocytes expressed less Fas/FasL than HT thyrocytes, whereas GD TILs had higher levels of Fas/FasL than HT TILs. GD thyrocytes expressed increased levels of the antiapoptotic molecule Bcl-2 compared to the low levels detected in HT thyrocytes. The opposite pattern was observed in GD (low Bcl-2) and HT (high Bcl-2) TILs. The patterns of apoptosis observed were consistent with the regulation of Fas, FasL, and Bcl-2 described above. Our findings suggest that in GD thyroid the regulation of Fas/FasL/Bcl2 favors apoptosis of infiltrating lymphocytes, possibly limiting their autoreactive potential and impairing their ability to mediate tissue damage. Moreover, the reduced levels of Fas/FasL and increased levels of Bcl-2 should favor thyrocyte survival and favor the thyrocyte hypertrophy associated with immunoglobulins stimulating the thyrotropin (TSH) receptor. In contrast, the regulation of Fas/FasL/Bcl2 expression in HT promotes thyrocyte apoptosis, tissue damage, and a gradual reduction in thyrocyte numbers leading to hypothyroidism. These findings help define key molecular mechanisms contributing to the clinical outcome of thyroid autoimmunity.
Thyroid 2001 Mar
PMID:Differential regulation of Fas-mediated apoptosis in both thyrocyte and lymphocyte cellular compartments correlates with opposite phenotypic manifestations of autoimmune thyroid disease. 1132 15

7-Hydroxystaurosporine (UCN-01) is a selective protein kinase C (PKC) inhibitor and is being developed as a novel anticancer agent. Because of reports that PKC may be involved in the pathogenesis of some forms of thyroid cancers, we examined four thyroid carcinoma lines (FRO, KAT5, NPA, and WRO). These cells were found to have different susceptibility to UCN-01 treatment, and there appeared to be a correlation between UCN-01-induced death and expression levels of endogenous Bcl-2. KAT5 cells, which normally express a low amount of Bcl-2, exhibited significantly higher sensitivity to UCN-01-induced death than the other cell lines. Of interest, susceptibility did not relate to PKC activity or its inhibition by UCN-01. In order to investigate the role of Bcl-2 in UCN-01-induced death, KAT5 cells were transfected to overexpress Bcl-2. KAT5/Bcl-2 cells were capable of conferring resistance to UCN-01-induced death. Furthermore, upregulating of Bcl-2 by 1alpha,25-dihydroxyvitamin D3 (VD3) could protect primary thyroid cell from death induced by UCN-01. Both in situ TUNEL staining and the flow cytometric analysis of cytokeratin-18 (CK18) cleavage confirmed that UCN-01 was indeed inducing apoptosis, and that this effect was inhibited by increased expression of Bcl-2. These results suggest that the Bcl-2 can block the UCN-01-activated cell death pathway and that the expression of Bcl-2 is inversely related to thyroid carcinoma cell susceptibility to UCN-01. Therefore, the analysis of the expression of apoptosis suppressors provides a basis for the use of UCN-01 in the treatment of thyroid cancer.
Thyroid 2001 Aug
PMID:Susceptibility of thyroid cancer cells to 7-hydroxystaurosporine-induced apoptosis correlates with Bcl-2 protein level. 1152 64


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