Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Medullary thyroid carcinoma (MTC) is a tumor of parafollicular cells of the thyroid gland. It has served as a useful experimental model for the study of tumor proliferation and differentiation. Although recent studies have identified the gene involved in familial forms of MTC, little is known about the molecular pathogenesis of the sporadic variants of this tumor. It has become increasingly clear that deregulation of programmed cell death is a critical component in multistep tumorigenesis. The present investigation was undertaken to determine whether similar molecular events occur in human MTC. Eighteen MTCs from 18 patients (including 12 sporadic and six familial cases and one metastatic lymph gland) and a MTC cell line (TT cells) were used in this study for detecting the expression of apoptosis-regulatory genes bcl-2, bax, c-myc, and p53. Immunohistochemical results showed that all MTC tumor samples displayed Bcl-2 and c-Myc immunoreactivity, whereas only 4 and 2 tumors showed a minority of cells positive for Bax and p53, respectively. Western and Northern blotting showed high levels of 26-kd Bcl-2 protein and bcl-2 transcript. The co-expression of Bcl-2 and c-Myc was also detected in the TT cells by indirect fluorescence immunohistochemistry and Western blotting. Moreover, Bcl-2 immunoreactivity was also found in C-cell hyperplasia from familial patients indicating that expression of this oncogene may represent an early event in the pathogenesis of MTC. The present study suggests that deregulation of programmed cell death may be a critical component in multistep tumorigenesis of MTC and that the frequent expression of the Bcl-2 oncoprotein in these tumors may contribute to their pathogenesis. The genetic complementation of simultaneously deregulated bcl-2 and c-myc may be implicated in the multistep tumorigenesis of human MTC.
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PMID:Bcl-2 and c-Myc, but not bax and p53, are expressed during human medullary thyroid tumorigenesis. 962 44

Constitutive expression of the c-myc proto-oncogene in growth factor-deprived fibroblasts promotes proliferation and induces apoptosis. In these cells, apoptosis can be inhibited by survival factors such as insulin-like growth factor I or the bcl-2 proto-oncogene product. Deregulated c-Myc expression is a common feature in Epstein-Barr virus-positive Burkitt's lymphoma in which the c-myc gene is reciprocally translocated and placed under the control of one of the immunoglobulin loci. BHRF1 is an Epstein-Barr virus protein expressed early in the lytic cycle. BHRF1 is a member of the Bcl-2 family and has been shown to suppress apoptosis and to increase cell survival in different settings. In the present study, we report that BHRF1 inhibits c-Myc-induced apoptosis which occurs in the absence of survival factors. It does not, however, affect the capacity of c-Myc to promote cell growth. These findings demonstrate that BHRF1 has not only structural but also functional similarities to Bcl-2.
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PMID:Suppression of c-Myc-induced apoptosis by the Epstein-Barr virus gene product BHRF1. 973 91

The activation of STAT3 by the cytokine receptor gp130 is required for both the G1 to S cell cycle transition and antiapoptosis. We found that Pim-1 and Pim-2 are targets for the gp130-mediated STAT3 signal. Expression of a kinase-defective Pim-1 mutant attenuated gp130-mediated cell proliferation. Constitutive expression of Pim-1 together with c-myc, another STAT3 target, fully compensated for loss of the STAT3-mediated cell cycle progression, antiapoptosis, and bcl-2 expression. We also identified valosine-containing protein (VCP) as a target gene for the Pim-1-mediated signal. Expression of a mutant VCP led cells to undergo apoptosis. These results indicate that Pim-family proteins play crucial roles in gp130-mediated cell proliferation and explain the synergy between Pim and c-Myc proteins in cell proliferation and lymphomagenesis.
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PMID:Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis. 1062 93

A series of B-cell lymphoma lines with an immature phenotype has been used as a model system to study molecular events associated with receptor ligation induced death. B-cell receptor (BCR) cross-linking with antibodies to membrane IgM (but not with anti IgD) induces c-Myc downregulation via nuclear factor kappaB inactivation and p27(Kip1) accumulation in these B lymphomas. Anti-mu-treated cells then undergo G1 arrest and die by apoptosis independent of Fas. Steroids and retinoids similarly downregulate c-Myc and induce apoptosis in these B cells and synergize with anti-mu. Rescue from apoptosis induced by anti-mu or steroids occurs with T-cell signals, like CD40L, or a broad-range caspase inhibitor, but only CD40L prevents the loss of c-Myc, p27 accumulation and growth arrest. Both IgM and IgD signaling lead to modulation of phosphatidylinositol 3-kinase (PI3K) signals, including the activation of p70(S6K), but this pathway recovers under anti-IgD treatment. Blockade of the PI3K pathway augments anti-mu-induced death and converts anti-delta to an apoptotic signal. Resistance to Fas-mediated death may be an important factor in B-cell transformation in vivo. Many of our panel of lymphomas are insensitive to Fas-mediated death signals, although all can form a death-inducing signaling complex (DISC). Additional studies suggest that some lymphomas can be blocked at the DISC complex by anti-apoptotic proteins, whereas others are inhibited downstream of caspase 8 activation. Anti-Ig treatment of a Fas-sensitive line, A20.2J, activated a number of genes whose products may block apoptosis proximally (like FLICE-inhibitory protein (FLIP1)) or at late points, such as bcl-2-family members. Our data suggest that B lymphomas develop multiple pathways of resistance to Fas-mediated signals during lymphomagenesis, in part via signaling through the BCR.
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PMID:B-cell receptor and Fas-mediated signals for life and death. 1104 71

A synergistic interaction of Bcl-2 and c-Myc plays a role in lymphomagenesis in mice and in some patients as well. Progression of follicular lymphoma to a more aggressive lymphoma is seen in the majority of patients, and approximately 10% of the transformed lymphomas have a translocation of c-myc in addition to the translocation of bcl-2 found in the original follicular lymphoma. We investigated whether transcriptional deregulation of bcl-2 and c-myc could be examined in primary lymphoma cells by in vivo footprinting and in vitro protein-DNA binding studies. A matched pair of follicular and transformed lymphoma samples was examined. The transformed lymphoma had acquired a translocation of c-myc into the immunoglobulin heavy chain locus. High levels of bcl-2 expression were observed in both the follicular and transformed lymphomas, whereas the expression of c-myc was low in the follicular lymphoma and increased in the transformed lymphoma. In vivo footprint analysis revealed that a CRE site and a Cdx site in the bcl-2 promoter were occupied on the translocated alleles but not on the normal alleles in both the follicular and transformed lymphomas. Two nuclear factor kappaB sites were occupied on the translocated c-myc allele in the transformed lymphoma. Gel shift analysis revealed that these proteins bound to their respective sites in the bcl-2 or c-myc promoter. There was no evidence that the presence of one of the translocations in the immunoglobulin heavy chain locus influenced the expression of the other translocated gene.
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PMID:Molecular mechanisms of transcriptional control of bcl-2 and c-myc in follicular and transformed lymphoma. 1143 60

The bcl-2 and c-myc oncogenes cooperate to transform multiple cell types. In the pediatric malignancy NB(2), Bcl-2 is highly expressed. In tumors with a poor prognosis, N-Myc, a protein homologous to c-Myc, is overexpressed as a result of gene amplification. The present study was designed to determine whether Bcl-2 cooperates with N-Myc to bestow a tumorigenic phenotype to neuroblastoma (NB) cells. NB cell lines that at baseline express neither Bcl-2 nor N-Myc were stably transfected to express these gene products. In this model, we found Bcl-2 rescues N-Myc-expressing cells from apoptosis induced by serum withdrawal. Coexpression of Bcl-2 and N-Myc supports growth in low serum conditions and anchorage-independent growth in soft agar. Similarly, in vivo tumorigenic and angiogenic activity was dependent on coexpression. Our data further suggests that the mechanism underlying these changes involves the receptor for insulin growth factor type I (IGF-IR).
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PMID:Bcl-2 and M-Myc coexpression increases IGF-IR and features of malignant growth in neuroblastoma cell lines. 1157 30

Benzamide riboside (BR) after anabolism to an analogue of NAD, was shown to inhibit the activity of NAD-dependent enzymes such as inosine 5'-monophosphate dehydrogenase (IMPDH), the rate limiting enzyme in de novo guanylate biosynthesis, and malate dehydrogenase which is involved in the citric cycle and respiratory chain. BR exhibits strong anti-carcinogenic effects due to growth retardation and due to induction of apoptosis and necrosis. Apoptosis is ascribed to the inhibition of IMPDH because cell death can be blocked by restoring intracellular guanylate metabolism by the addition of guanosine. It is shown here, however, that also survival-relevant genes such as cdc25A, akt, bcl-2 and transferrin receptor become repressed by BR, whereas the expression level of the apoptosis enforcing gene c-myc persists. Even though BR-mediated growth retardation still allows BR to induce apoptosis, rapamycin-mediated cell cycle block and cell contact inhibition prevent cell death, it strongly suggests that BR induces a type of c-Myc-dependent apoptosis. At high concentrations BR induces DNA double strand breaks by yet to be determined mechanisms that occur hours before necrosis can be detected. This is accompanied by a dramatic decrease of intracellular ATP. The artificial restoration of ATP by addition of adenosine or sufficient provision of an energy source such as glucose prevents BR-promoted necrosis and favors apoptosis. This observation may be of clinical relevance.
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PMID:Potential mechanisms of benzamide riboside mediated cell death. 1196 40

Penta-acetyl geniposide, (Ac)5-GP, the acetylated compound of geniposide, is able to inhibit the growth of rat C6 glioma cells in culture and in the bearing rats. Our recent data indicated that the induction of cell apoptosis and cell cycle arrest at G0/gap phase 1 (G1) by (Ac)5-GP might be associated with the induction of p53 and c-Myc, and mediated via the apoptosis-related bcl-2 family proteins. In this report, we further investigated the mechanism involved in the cell cycle arrest induced by (Ac)5-GP in C6 glioma cells. The inhibitory effect of (Ac)5-GP on the cell cycle progression of C6 glioma cells which arrested cells at the G0/G1 phase was associated with a marked decrease in the protein expression of cyclin D1, and an induction in the content of cyclin-dependent kinase (cdk) inhibitor p21 protein. This effect was correlated with the elevation in p53 levels. Further immunoprecipitation studies found that, in response to the treatment, the formation of cyclin D1/cdk 4 complex declined, preventing the phosphorylation of retinoblastoma (Rb) and the subsequent dissociation of Rb/E2F complex. These results illustrated that the apoptotic effect of (Ac)5-GP, arresting cells at the G0/G1 phase, was exerted by inducing the expression of p21 that, in turn, repressed the activity of cyclin D1/cdk 4 and the phosphorylation of Rb.
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PMID:Inhibition of cell cycle progression by penta-acetyl geniposide in rat C6 glioma cells. 1520 44

Congenital melanocytic nevi (CMN) occur in 1% to 2% of newborns, and the risk of malignant melanoma is increased in patients with large CMN. Appearance at birth or later of a nodular or hyperpigmented area within a CMN simulates malignant melanoma and prompts biopsy. Although their clinical and pathologic features seem ominous, proliferative nodules (PNs) typically are benign and may regress, although atypical features cause greater concern. Here we report clinical and pathologic findings with outcome in 10 children who had multiple biopsies of large CMN with PNs. We reviewed 78 separate samples from the 10 patients and classified the 60 PNs according to published criteria. A subset of 30 samples containing both the CMN and a PNs was analyzed for immunohistochemical reactivity for melanocytic (S-100 protein, HMB45, melan-A), lymphocytic (CD45), cell-cycle/proliferative (Mib-1, p16, p21, p27, c-Myc), apoptotic (p53, Bax, c-kit, CD95), and anti-apoptotic (bcl-2) markers. Both CMN and PNs had similar expression of melanocytic, lymphocytic, and most cell-cycle/proliferative and apoptotic markers, including Mib-1, p16, p21, p27, c-Myc, Bax, CD95, and bcl-2. A greater proportion of PNs than CMN were reactive for p53 (67% vs. 30%, P < 0.0098) and c-kit (97% vs. 3%, P < 0.0001). p53 and p21 expression in CMN and all types of PNs were inversely correlated. When ordinary and atypical PNs were compared, the atypical PNs more frequently expressed p53, Mib-1, Bax, and bcl-2, but less frequently expressed p21. The c-kit expression in nearly all PNs and its absence in nearly all CMN is potentially useful for recognition of PN, suggests a delayed melanocytic maturation process in proliferative nodules, and may be likely indicative of their benign nature. p53 reactivity in concert with a lack of p21 up-regulation by immunohistochemistry suggests that a p53 mutation may be present in PN, although the immunohistochemical findings alone cannot exclude possible overexpression of wild-type p53. Regressive, involutional, or maturational changes were observed in sequential samples from 4 patients. No patient developed malignant melanoma or another melanocytic nevus-associated malignancy during the follow-up period. These findings underscore the similarities between PNs and the underlying CMN and suggest that maturational, proliferative, and apoptotic processes are involved in their clinical evolution.
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PMID:Proliferative nodules in congenital melanocytic nevi: a clinicopathologic and immunohistochemical analysis. 1525 7

Zinc is involved in many physiological processes and plays a critical role in functional and structural cells. Zinc at concentrations ranging from 100 to 150 micromol L(-1) has been shown to induce morphological transformation of Syrian hamster embryo (SHE) cells. At these concentrations, zinc inhibited apoptosis in SHE cells. The objective of this study was to elucidate the mechanisms of action of zinc on the apoptotic pathway. Effects of 100 and 150 micromol L(-1) ZnCl(2) on the expression of two members of the Bcl-2 family of proteins and on the transcription factor c-Myc in SHE cells was investigated using RT-PCR. No effect on the proto-oncogene c-myc was observed. Up-regulation of bcl-2 expression was found and bax expression was reduced. These changes have been corroborated by immunoblotting. Effects of Zn(2+) on bcl-2/bax ratio were confirmed in apoptotic camptothecin-treated SHE cells. Cloned and sequenced cDNAs obtained from RT-PCR amplifications allowed us to check the RT-PCR products encoded the expected proteins. This study demonstrated that zinc acts in the early phases of the apoptotic process by modification of the bcl-2/bax ratio in normal and apoptotic SHE cells.
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PMID:Changes in expression of bcl-2 and bax in Syrian hamster embryo (SHE) cells exposed to ZnCl2. 1555 Oct 63


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