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)

Chromosomal translocation within B and T cell malignancies has proven a rich source for proto-oncogenes. The obligate DNA breaks within immunoglobulin (Ig) and T cell receptor (TCR) loci are frequently the sites of recurrent translocations. Burkitt's lymphoma established the paradigm by introducing the myc oncogene from chromosome segment 8q24 into the Ig heavy chain gene locus at 14q32. Molecular cloning of an aberrant Ig rearrangement in follicular lymphoma revealed Bcl-2. Bcl-2 constitutes the first member of a new category of oncogenes: regulators of programmed cell death. Bcl-2 blocks apoptosis and maintains long-term immune responsiveness including B-cell memory. The PRAD1 gene of parathyroid adenomas appears to be the elusive Bcl-1 gene of t(11;14)(q13;q32) bearing lymphomas. It proves to be a novel G1 cyclin. Acute lymphoblastic leukemias (ALL) pre-B phenotype produce a E2A/PBX fusion protein that possesses the leucine zipper of E2A with the homeodomain of PBX. Two molecular forms of the BCR/ABL fusion protein are produced by the Philadelphia chromosome. A deregulated p210 tyrosine kinase is found in chronic myelogenous leukemia, while a p190 form predominates in Ph+ ALL. In contrast, T-cell ALLs introduce a potpourri of genes into their T cell receptor loci. However, a common theme is emerging. These oncogenes (Ttg1, Ttg2, SCL, LylI, H0X11) all belong to classic families of transcription factors, possessing LIM domains, helix-loop-helix motifs, or homeodomains. Provocatively, these transcription factors are normally intended for lineages other than T cells. These genes have widened the horizons of both oncogenesis and normal development.
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PMID:Chromosomal translocations in lymphoid malignancies reveal novel proto-oncogenes. 159 Oct 3

Bcl-2 is an inner mitochondrial membrane protein which blocks apoptosis. Although present in many B cells, the vast majority of follicular center cells do not have detectable bcl-2 protein. The bcl-2 gene is translocated in most conventional small cleaved follicular center cell (SCFCC) lymphomas (centroblastic/centrocytic) but not in centrocytic lymphomas (CC). The translocated gene in the SCFCC lymphomas leads to 'aberrant' bcl-2 expression by the neoplastic follicular center cells. The frequency with which the normal non-translocated gene is expressed in CC lymphomas is, however, not well documented. Paraffin sections from 22 cases of centrocytic lymphoma were therefore stained with an anti-bcl-2 antibody. Genotypic studies in 14 cases demonstrated bcl-1/PRAD1 (cyclin D1; CCND1) rearrangements in ten and bcl-2 rearrangements in none. All centrocytic lymphomas demonstrated bcl-2 protein expression in the majority of neoplastic cells. Negative staining residual follicular centers were identified in four cases emphasizing the mantle zone growth pattern of a subset of CC lymphomas. Expression of bcl-2 protein in the absence of bcl-2 gene rearrangement is a feature shared by centrocytic lymphomas and mantle zone cells. However, because this type of bcl-2 expression is not specific for B-cells of the mantle zone, it does not further elucidate the true cell of origin for the centrocytic lymphomas.
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PMID:Bcl-2 protein in centrocytic lymphoma; a paraffin section study. 837 94

Two human herpesviruses, HHV-6 and HHV-7, recently identified and closely related, were studied for their influence on cellular apoptosis and proliferation. Infection was monitored by viral DNA--and antigen expression. Apoptosis and cell proliferation were determined by immunocytological techniques and the markers p53, p21WAF/Cip, Bax, Bak, Bcl-2, cyclin D1 and PCNA, and also screened for signal transduction indicators such as c-H-ras, c-fos and raf-1. Cell differentiation and function was monitored by determining cell membrane receptors including Fas and CD specificities, and by ELISA tests for interleukin production. Both HHV-6 and HHV-7 readily infected their target cells, yet virus antigen expression and virus replication were less active in HHV-7 infection. Both viruses also induced GM-CFS production. Cell differentiation in terms of CD receptor expression was more pronounced in HHV-6 than in HHV-7 infection. No differences were found in the activity of signal transduction factors. There were quantitative differences in the activation of p53, Bax, p21WAF and Bcl-2 in HHV 6-infected CBC as compared to HHV-7 infection supporting the apoptosis cycle. CyclinD1 activity remained at lower levels in HHV-7 infected CBC, yet was high in similarly infected transformed SupT1 cells. In contrast, HHV-6 supported rather the p53/p21WAF apoptosis pathway in both untransformed CBC and transformed HSB1 cells. Both herpesviruses, HHV-6 and HHV-7, thus possessed similar biological activities in cultures of non-transformed susceptible cells, although with certain quantitative differences. The data reported here may further support the notion that HHV-7 is less active in inducing apoptosis thus favoring continued cell proliferation. The mechanism by which these viruses interfere with the network control of cell proliferation, differentiation and apoptosis appear more complicated than shown here and therefore afford a more detailed study, including a more sensitive technology than immunohistology.
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PMID:In vitro cytobiological effects of human herpesviruses 6 and 7: immunohistological monitoring of apoptosis, differentiation and cell proliferation. 949 80

Previously, we demonstrated that inostamycin, an inhibitor of phosphatidylinositol turnover, caused cell cycle arrest at the G1 phase, inhibiting the expression of cyclins D1 and E in normal cells. In the present study, we examined the effects of inostamycin on cell cycle progression and apoptosis in human small cell lung carcinoma Ms-1 cells. Treatment of exponentially proliferating Ms-1 cells with low concentrations of inostamycin caused cells to accumulate in the G1 phase. We found that inostamycin decreased cyclin D1, and increased cyclin-dependent kinase inhibitors such as p21WAF1 and p27KIP1 in Ms-1 cells. On the other hand, higher concentrations of inostamycin induced morphological apoptosis and DNA fragmentation in Ms-1 cells without affecting the expression of p53, Bcl-2 and Bax. Inostamycin-induced apoptosis was suppressed by an inhibitor of caspase-3, and a 17 kDa fragment of activated caspase-3 was detected following inostamycin treatment. Therefore, caspase-3(-like) would appear to be involved in inostamycin-induced apoptosis. On the other hand, an inhibitor of caspase-3(-like) proteases did not affect the inhibitory effect of inostamycin on cyclin D1 expression, suggesting that caspase-3(-like) proteases were not responsible for inostamycin-induced G1 arrest.
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PMID:Inhibition of cyclin D1 expression and induction of apoptosis by inostamycin in small cell lung carcinoma cells. 960 Jan 26

A mantle cell lymphoma (MCL) cell line (JeKo-1) was established from peripheral blood mononuclear cells of a patient with a large cell variant of MCL showing leukaemic conversion. JeKo-1 cells were Epstein-Barr virus negative and showed a B-cell phenotype with IgM+, IgD+, CD3-, CD5+, CD10-, CD19+, CD20+ and CD23-; they overexpressed cyclin D1, Bcl-2, c-Myc and Rb proteins. Bcl-1/J(H) gene rearrangement was confirmed by polymerase chain reaction, although karyotypic analysis showed 40/41 chromosomes devoid of apparent t(11;14)(q13;q32) translocation. JeKo-1 cells were highly tumourigenic in SCID mice.
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PMID:Establishment and characterization of a mantle cell lymphoma cell line. 975 63

Apoptosis is a mechanism of cell death that occurs in normal development and on the regulation of vertebrate tissues and organ cellularity. Neurons undergo p53-dependent and p53-independent apoptosis, depending upon the stimulus that triggers DNA fragmentation. Many neurons in the developing nervous system suffer apoptosis, with the cyclin D1 being an essential mediator of neuronal cell death. Other characteristics of apoptosis are: condensation of the nucleus, fragmentation of chromatin at nucleosome linkage sites, membrane blebbing, and the formation of apoptotic bodies. Among the possible molecular mechanisms are: (a) activation of proteases, as ICE (Il-1 beta converting enzyme); (b) calpain is activated in several cells, with PARP (Poly-ADP-ribose polymerase) and a small U1 Ribonucleoprotein, being substrates for ICE and its homologs such as ICH and others proteins. The p53 gene encodes a transcription factor that contributes to several different cellular activities, including apoptosis, the cellular response to radiation, and the activation of proteins such as GADD, Bcl-2 (represses to apoptosis) and Bax. P53 exerts a role as inductor of apoptosis by transactivating expression of the Bax gene. The p53 gene tumor suppressor limits cellular proliferation by including either the arrest of cell cycle in G1, or apoptosis, depending on the cellular context. The p21 is an inhibitor of cyclin-dependent kinase, which is transactivated by p53. During apoptosis, there is an activation of both, c-myc, and the transcription factor NF-kB, which is a important regulator of apoptosis. As an example of signalization of apoptosis we have selected to illustrate the problem related to the system Fas/APO in thymocytes.
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PMID:[Molecular bases of the programmed cell death process: implications of tumor suppressor protein p53 and other proteins in the control of cell cycle. Mechanisms of apoptotic action. Review]. 992 5

Endocrine treatments for human breast cancer have been based largely upon the removal of estrogenic stimuli. The regression of tumors after estrogen deprivation has generally been characterized as being due to reduced proliferation but more recently has been recognized to also involve increased apoptosis. The aim of our experiments was to define the associated changes in certain proliferation- and cell death-related biological parameters after hormone withdrawal from estrogen-dependent MCF-7 xenografts in athymic nude mice using immunohistochemical techniques. The baseline estrogen receptor (ER) level of this MCF-7 xenograft was relatively low (average H score 23) but it was strongly Bcl-2-, PgR- and pS2-positive, indicating the functional integrity of estrogen signaling. Changes in proliferation (Ki-67), apoptosis, ER, progesterone receptor (PgR), cyclin D1, p27kip1, Bcl-2 and Bax expression were assessed during the 2 weeks after estrogen deprivation. ER levels rose markedly after estrogen ablation, whereas PgR levels fell to about 10% of baseline and pS2 levels halved. The proportion of Ki-67-positive cells was unchanged after 24 hr but by day 14 had reduced by about 80%. The normal levels of cyclin D1 also reduced after estrogen withdrawal in contrast to the rapid increase in levels of cyclin-dependent kinase inhibitor p27kip1. This latter increase appeared to occur in advance of the changes in Ki-67. The proportion of apoptotic cells increased from a mean 1.5% at baseline to 2.9% after 3 days and 4.7% after 14 days. There were reductions in both Bcl-2 and Bax staining but these appeared to be greater for Bcl-2, effectively decreasing the Bcl-2/Bax ratio. Our results provide a framework for the use of these parameters as intermediate markers in comparisons of hormonal agents for human breast cancer treatment.
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PMID:Time-related effects of estrogen withdrawal on proliferation- and cell death-related events in MCF-7 xenografts. 1018 36

p27Kip1, a cyclin-dependent kinase inhibitor, is a negative regulator of the cell cycle, and apoptosis is a genetically encoded program of cell death. To clarify the relationship between the cell cycle and apoptosis, we investigated expression of p27, cyclin D1 and apoptosis-related proteins (p53, Bax, Bcl-2 and c-Myc) in 60 cases of oral and oropharyngeal squamous-cell carcinoma (SCC) using an immuno-histochemical approach, and evaluated spontaneous apoptosis in vivo. Our most notable finding was that spontaneous apoptosis in the p27-positive group was significantly higher than that in the p27-negative group (p = 0.028). In addition, the percentage of p27-positive cells was clearly correlated with that of Bax-positive cells (gamma = 0.288, p = 0.028) and with that of cyclin D1-positive cells (gamma = 0.416, p = 0.002). Expression of p27 was inversely associated with the clinical stage of total tumor progression (p = 0.027). However, no correlation was found between p27 expression and the following parameters: gender, tumor size, lymph node metastasis, overall survival and disease-free survival. Our results give evidence that the action of the cell-cycle regulator p27 is closely linked with apoptosis in clinical samples from patients and indicate that over-expression of p27 might induce apoptosis in cancer cells through elevation of Bax expression, thereby acting on tumor progression.
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PMID:Expression of p27 is associated with Bax expression and spontaneous apoptosis in oral and oropharyngeal carcinoma. 1037 53

Reduction in serum prostate-specific antigen (PSA) levels has been proposed as an endpoint biomarker for hormone-refractory human prostate cancer intervention. We examined whether a flavonoid antioxidant silibinin (an active constituent of milk thistle) decreases PSA levels in hormone-refractory human prostate carcinoma LNCaP cells and whether this effect has biological relevance. Silibinin treatment of cells grown in serum resulted in a significant decrease in both intracellular and secreted forms of PSA concomitant with a highly significant to complete inhibition of cell growth via a G1 arrest in cell cycle progression. Treatment of cells grown in charcoal-stripped serum and 5alpha-dihydrotestosterone showed that the observed effects of silibinin are those involving androgen-stimulated PSA expression and cell growth. Silibinin-induced G1 arrest was associated with a marked decrease in the kinase activity of cyclin-dependent kinases (CDKs) and associated cyclins because of a highly significant decrease in cyclin D1, CDK4, and CDK6 levels and an induction of Cip1/p21 and Kip1/p27 followed by their increased binding with CDK2. Silibinin treatment of cells did not result in apoptosis and changes in p53 and bcl2, suggesting that the observed increase in Cip1/p21 is a p53-independent effect that does not lead to an apoptotic cell death pathway. Conversely, silibinin treatment resulted in a significant neuroendocrine differentiation of LNCaP cells as an alternative pathway after Cip1/p21 induction and G1 arrest. Together, these results suggest that silibinin could be a useful agent for the intervention of hormone-refractory human prostate cancer.
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PMID:Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. 1037 42

Time-dependent ladder-type DNA fragmentation and morphological alterations consistent with apoptosis were observed among A253 human head and neck squamous cell carcinoma (HNSCC) cells in nude mice from 15 to 18 days after transplantation, without any drug treatment. No evidence of ladder-type DNA fragmentation was detected in A253 cells in vitro or in normal nude mouse tissues (skin and muscle). Our aim was to explore molecular factors associated with such spontaneous apoptosis. Bcl-2 protein expression decreased, while bax protein expression increased from day 9 after transplantation. Moreover, altered expression of bcl-2 and bax was accompanied by the increased proteolytic cleavage of poly(ADP-ribose) polymerase (PARP). Time-dependent dephosphorylation of Rb, followed by proteolytic cleavage, was also observed from day 9 after transplantation. The data indicate that the caspase-3 activation and cleavage of Rb protein may represent important steps in the regulation pathway of bax-mediated spontaneous apoptosis. Interestingly, the time-dependent activation of spontaneous apoptosis was almost simultaneous with the induction of differentiation and increased expression of several differentiation-associated regulatory proteins. An increased expression of cyclin D1 and cyclin-dependent kinase-5 (cdk5) was observed from day 9 after transplantation, whereas only slight alteration of cdk4 expression was found. The time-dependent activation of cyclin D1 and cdk5 preceded both the induction of ladder-type DNA fragmentation and increased keratin pearl formation. Furthermore, MCM3 was cleaved early in spontaneous apoptosis and differentiation. Our observations suggest the involvement of cyclin D1-cdk5 overexpression and MCM3 cleavage in bax-mediated spontaneous apoptosis and differentiation in A253 xenografts. P53 and WAF1 proteins were not expressed in the xenografts, indicating that the changes in the regulatory proteins during apoptosis and differentiation were not p53 or WAF1 dependent.
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PMID:Involvement of cyclin D1-cdk5 overexpression and MCM3 cleavage in bax-associated spontaneous apoptosis and differentiation in an A253 human head and neck carcinoma xenograft model. 1049 26


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