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)

Interleukin 2 (IL-2)- and IL-4-mediated stimulation of survival and growth, reflected by the induction of bcl2 and c-myc, respectively, depends on the integrity of the membrane-proximal region (S-region) in the IL-2 receptor beta-chain (IL-2R beta) and the haematopoietin homology box1-containing region of the IL-4 receptor alpha-chain (IL-4R alpha). In contrast to IL-4, IL-2 induces the expression of c-fos and c-jun family genes, mediated by the acidic region (A-region) within the cytoplasmic domain of IL-2R beta. A highly acidic motif is also present in IL-4R alpha, and evidence in favour and against its importance has been published. The authors have constructed chimeric receptors between IL-2R beta and IL-4R alpha by substitution of either the S-region or the A-region of IL-2R beta with sequences derived from IL-4R alpha. These chimeras were stably transfected into BA/F3 cells and assayed for the capacity to restore functions of IL-2 beta, such as growth mediation by IL-2 and the induction of proto-oncogenes (c-myc, c-junB and c-fos). Replacement of both the S- and A-region of IL-2R beta with IL-4R alpha derived regions of similar size and cytoplasmic location supported growth-stimulation by IL-2 as well as proto-oncogene induction. In contrast, all IL-2R functions were lost by exchange of the S-region with the corresponding part of IL-4R alpha. Induction of c-junB and c-fos RNA as an indicator of A-region function, however, was maintained in an IL-2R beta chimera containing the acidic box-bearing region of IL-4R alpha. These data indicate a functional role of the acidic region in the IL-4R alpha-chain.
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PMID:Function of the human interleukin 4 receptor (IL-4R)-derived acidic motif revealed by cytoplasmic domain chimeras of the IL-4R alpha chain and the IL-2R beta chain. 961 70

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

Isolated murine splenic B cells undergo spontaneous apoptosis. Motifs containing unmethylated CpG dinucleotides in bacterial DNA or in synthetic oligodeoxynucleotides (ODN) are known to activate murine B cells. Now we show that ODN that induce spleen B cell cycle entry also inhibit spontaneous apoptosis in a sequence-specific fashion. Reversal of the CG to GC abolished activity. Methylation of the central cytosine decreased activity. When CpG is preceded by a cytosine or followed by a guanine, activity was abolished. Other substitutions at the same positions had no effect. Dose-response curves for apoptosis protection and G1 entry suggested that a uniform population of ODN recognition sites controlled downstream ODN effects. A CpG ODN with a nuclease-resistant phosphorothioate backbone (S-ODN) was also active, and increased the levels of c-myc, egr-1, c-jun, bclXL, and bax mRNA and c-Myc, c-Jun, Bax, and BclXL protein in spleen B cells. Levels of c-myb, myn, c-Ki-ras, and bcl2 mRNA remained unchanged. When protein synthesis was inhibited, at 16 h ODN-induced cell cycle entry was abolished and apoptosis protection was partially preserved. Under these conditions, c-Myc was still present, but c-Jun and BclXL were not detected. Our results suggest that CpG containing ODN motifs provide signals for both survival and cell cycle entry. Single base changes determine whether this signal proceeds through a rate-limiting step governing at least two steps in apoptosis (plasma membrane transition, DNA cleavage) and two phases of the cell cycle (G1 and S phase entry). This biologic action is associated with increased c-Myc, c-Jun, and BclXL expression.
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PMID:CpG oligodeoxyribonucleotides rescue mature spleen B cells from spontaneous apoptosis and promote cell cycle entry. 963 2

We have previously shown that metastatic carcinomas of unknown primary site overexpress several tumor markers as well as the products of the oncogenes c-myc, ras and c-erbB2. We analyzed the tissue expression of the protein products of the apoptosis modulation genes p53 and bcl-2 in 47 CUP cases. Formalin-fixed, paraffin embedded tumor specimens were stained with commercially available antibodies to p53 (DO7) and bcl-2 after antigen retrieval by the microwave method. Staining was evaluated by intensity (1+ to 3+), percentage of positive cells (1-100%), and the 'intensity times percentage' product defined as the immunoreactivity index with values ranging from 0 to 300. Immunoreactivity index values higher than 150 were considered to characterize protein over-expression. Expression of p53 was identified in 70.2% of tumors while 53% of them showed a high immunoreactivity index. Bcl-2 expression was detected in 65% of tumors and overexpressed in 40%. Overexpression of both proteins was detected in 20% of tumors. The detection of either protein was not associated with any of the major clinicopathological variables studied. Nevertheless, a trend towards a more favourable response to platin based chemotherapy was seen in the cases that showed a strong expression of both proteins, when analysed by immunoreactivity index and percentage of positive cells. We conclude that CUP overexpress at a high percentage the p53 and the bcl2 proteins. The observed weak association of strong expression of these proteins with response to platin-based chemotherapy deserves further evaluation in the CUP setting.
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PMID:Bcl2 and p53 protein expression in metastatic carcinoma of unknown primary origin: biological and clinical implications. A Hellenic Co-operative Oncology Group study. 967 43

The c-myc oncoprotein accelerates programmed cell death (apoptosis) after growth factor deprivation or pharmacological insult in many cell lines. We have shown that max, the obligate c-myc heterodimeric partner protein, also promotes apoptosis after serum withdrawal in NIH3T3 fibroblasts or cytokine deprivation in interleukin-3 (IL-3)-dependent 32D murine myeloid cells. We now show that c-myc- and max-overexpressing 32D cells differ in the nature of their apoptotic responses after IL-3 removal or treatment with chemotherapeutic compounds. In the presence of IL-3, c-myc overexpression enhances the sensitivity of 32D cells to Etoposide (Sigma, St Louis, MO), Adriamycin (Pharmacia, Columbus, OH), and Camptothecin (Sigma), whereas max overexpression increases sensitivity only to Camptothecin. Drug treatment of c-myc-overexpressing cells in the absence of IL-3 did not alter the spectrum of drug sensitivity other than to additively accelerate cell death. In contrast, enhanced sensitivity to Adriamycin, Etoposide, and Taxol (Bristol-Meyers Squibb, Princeton, NJ) was revealed in max-overexpressing cells concurrently deprived of IL-3. Differential rates of apoptosis were not strictly correlated with the ability of the drugs to promote G1 or G2/M arrest. Ectopic expression of Bcl-2 or Bcl-XL blocked drug-induced apoptosis in both cell lines. In contrast, whereas Bcl-2 blocked apoptosis in both cell lines in response to IL-3 withdrawal, Bcl-XL blocked apoptosis in max-overexpressing cells but not in c-myc-overexpressing cells. These results provide mechanistic underpinnings for the idea that c-myc and max modulate distinct apoptotic pathways.
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PMID:Distinct apoptotic responses imparted by c-myc and max. 968 Mar 70

Burkitt's lymphoma cells that vary in their phenotypic characteristics show significantly different degrees of susceptibility to radiation-induced apoptosis. Propensity to undergo apoptosis is reflected in the degradation of substrates such as DNA-dependent protein kinase but the status of bcl-2, c-myc and p53 has been uninformative. In this study, we have focused on 2 Epstein-Barr virus (EBV)-associated Burkitt's cell lines, one (WW2) susceptible and the other (BL29) resistant to etoposide-induced apoptosis. Differences in expression of BHRF1, an EBV gene that is homologous to the Bcl-2 proto-oncogene and known to inhibit apoptosis, or changes in apoptosis inhibitory proteins (IAPs), did not appear to account for the difference in susceptibility in the 2 cell lines. Cytoplasmic extracts from etoposide-treated WW2 cells caused apoptotic changes in nuclei isolated from either BL29 or WW2 cells, whereas extracts from BL29 cells failed to do so. In addition, extracts from etoposide-treated WW2 cells degraded the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), an important indicator of apoptosis, but this protein was resistant to degradation by BL29 extracts. It appears likely that caspase 3 (CPP32) is involved in this degradation since it was activated only in the apoptosis susceptible cells and the pattern of cleavage of DNA-PKcs was similar to that reported previously with recombinant caspase 3. As observed previously, addition of caspase 3 to nuclei failed to induce morphological changes indicative of apoptosis, but addition of caspase 3 to nuclei in the presence of extract from the resistant cells led to apoptotic changes. We conclude that resistance to apoptosis in BL29 cells is due to a failure of etoposide to activate upstream effectors of caspase activity.
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PMID:Resistance to etoposide-induced apoptosis in a Burkitt's lymphoma cell line. 968 10

Ninety-six cutaneous melanomas (CMs) were investigated aiming at finding differences, if any, among the main four clinicopathological types, for Bcl-2, c-myc and p53 protein expression, and for tumor cell proliferation and death indices. Proliferation was assessed by calculating the mitotic index (MI, number of mitoses) and the MIB1 labelling index (M-LI, number of MIB1+ nuclei), and tumor cell death by calculating the apoptotic index (AI, number of apoptoses) among 1000 tumor cells. CMs were subdivided into thin (<1 mm) and intermediate thickness (1-4 mm) tumors. Bcl-2 expression did not significantly change among different types. c-myc Expression decreased especially in thicker superficial spreading (SSM) and lentigo maligna melanoma (LMM) types. p53 Expression was higher in nodular melanoma (NM) and in acral lentiginous melanoma(ALM), which also showed the highest degrees of proliferation. AI was significantly higher in thin rather than in intermediate thickness SSMs, LMMs and ALMs (8.4 vs. 2; 6.1 vs. 2.3, and 5.8 vs. 3.6, respectively). AI was low in thin (1.7) and intermediate thickness (1.9) NMs, which also showed high MI (3.9 and 4.5, respectively), and M-LI (16.7 and 2.9, respectively). Thin and intermediate thickness ALMs also showed high MI and M-LI (4.1 vs. 5.2 and 11.3 vs. 14.6, respectively). Bcl-2 is among genes which inhibit apoptotic death, whereas c-myc and p-53 genes promote this process. In CMs, no relation was found between Bcl-2 expression, MI, PI, and AI. All SSMs, LMMs, and ALMs with a high AI showed a high c-myc expression and were negative for p53. c-myc, Although highly expressed, did not promote a significant apoptotic death in NM type. Bc12, c-myc, and p53 were not equally expressed nor equally related to tumor cell turnover in all CMs, suggesting their different influence on the various types and stages, and the role of other factors in CM growth control.
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PMID:Different patterns of cell proliferation and death and oncogene expression in cutaneous malignant melanoma. 969 89

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

c-, N-, and L-myc are related nuclear oncoproteins that bind similar DNA sites and cooperate with activated ras oncogenes to transform primary fibroblasts. Although c-myc can also promote apoptosis in some cells after growth factor withdrawal or exposure to cytotoxic agents, roles for N- and L-myc in apoptosis remain undetermined. To address this, c-, N-, or L-myc were stably expressed in the interleukin 3 (IL-3)-dependent 32D hematopoietic cell line. The apoptotic response of each cell line was assessed after IL-3 withdrawal or treatment with four structurally unrelated cytotoxic agents. All three oncoproteins accelerated apoptosis after IL-3 withdrawal. In contrast, whereas c-myc overexpression generally sensitized cells to cytotoxic drugs, N-myc and L-myc overexpression produced resistance. myc expression tended to be associated with a more robust G2-M arrest after drug exposure, but this did not correlate with drug sensitivity or resistance. Bcl-2 and Bcl-X(L) protected control cells against apoptosis after either IL-3 withdrawal or drug exposure, although in some cases this effect could be overridden by myc oncoproteins, particularly N-myc and L-myc. Our results suggest that the apoptotic pathways activated upon IL-3 withdrawal and cytotoxic drug treatment are distinct and differentially affected by members of the myc and Bcl-2 families.
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PMID:Differential apoptotic behaviors of c-myc, N-myc, and L-myc oncoproteins. 975 Nov 17

The activities of 2-chlorodeoxyadenosine (2-CdA) metabolizing enzymes, deoxycytidine kinase (dCK) and cytosolic 5'-nucleotidase (5'-NT) were measured in control and bryostatin 1 treated CLL cells using an EBV-negative WSU-CLL cell line. This cell line was established from a patient with CLL resistant to fludarabine. The results revealed a significant increase in dCK activity in bryostatin 1 treated cells at 48 and 72 h compared with the control. 5'-NT activity decreased significantly at 48 h. The ratio of dCK to 5'-NT activity was significantly increased in bryostatin 1 treated WSU-CLL cells after 48 h. WSU-CLL cells treated with bryostatin 1 exhibited an increase in the percentage of apoptotic and dead cells from control levels of 16% to 40%. This percentage was further increased to 67% following the addition of 11.2 microM 2-CdA to WSU-CLL cells pretreated with bryostatin 1. Results from Western blot analysis indicate that WSU-CLL cells express high levels of Bcl-2, Bcl-xL and c-myc, and a low level of Bax. p53 in untreated WSU-CLL cells is undetectable. WSU-CLL cells treated with bryostatin 1 showed a significant increase in the ratio of Bax to Bcl-2. To demonstrate that the bryostatin 1 mediated enhancement of 2-CdA efficacy was not restricted to in vitro cell culture, we have studied the tumor growth delay of WSU-CLL xenografts treated with placebo, bryostatin 1, 2-CdA, and bryostatin 1 followed by 2-CdA. SCID mice given bryostatin 1 at 75 microg x kg(-1) x d(-1) for 5 days followed by 30 mg x kg(-1) x d(-1) 2-CdA for 5 days in two cycles, had significantly improved tumor growth delay (P = 0.05). We conclude that bryostatin 1 is not only capable of inducing apoptosis by itself, but also sensitizes de novo resistant WSU-CLL cells to the chemo-therapeutic effects of 2-CdA. The bryostatin 1-induced increased ratio of dCK/5'-NT activity and an increased ratio of Bax/Bcl-2 are at least two mechanisms through which this natural compound is able to potentiate the anti-tumor activity of 2-CdA in otherwise resistant CLL cells.
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PMID:Potentiation of 2-chlorodeoxyadenosine activity by bryostatin 1 in the resistant chronic lymphocytic leukemia cell line (WSU-CLL): association with increased ratios of dCK/5'-NT and Bax/Bcl-2. 982 May 86


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