Disease relevance of BCL2

• Clinically, primary human melanoma expression microarrays revealed tight nearest neighbor linkage for MITF and BCL2 [1].
• Molecular analysis showed that BCL2 was rearranged in the major breakpoint cluster region and had joined into the immunoglobulin heavy chain gene as in follicular lymphoma [2].
• We have analyzed the oncogene rearrangements involving BCL2 and MYC in the leukemia cells of a patient with an aggressive prolymphocytic leukemia that had an abnormal karyotype including a t(14;18) translocation and a chromosome 17q+ [2].
• It remains to be established whether these somatic mutations that alter BCL2 proteins influence the pathobiology of nonHodgkin's lymphomas [3].
• B-cell non-Hodgkin's lymphoma cell line (Karpas 1106) with complex translocation involving 18q21.3 but lacking BCL2 rearrangement and expression [4].
• Pretreatment Bcl2 expression was specifically associated with distant metastasis; five of six distant metastases occurred in the <40% of patients whose primary tumors were Bcl2 positive [5].

Psychiatry related information on BCL2

• The expression of anti-apoptotic Bcl2 correlated with observed cell death in T-helper and B cells irrespective of dementia [6].

High impact information on BCL2

• Moreover, BCL-XL, BCL-2, and BAX can form ion-conductive pores in artificial membranes [7].
• An expanding family of BCL-2 related proteins share homology, clustered within four conserved regions, namely BCL-2 homology (BH1-4) domains, which control the ability of these proteins to dimerize and function as regulators of apoptosis [7].
• BID and BAD possess the minimal death domain BH3, and the phosphorylation of BAD connects proximal survival signals to the BCL-2 family [7].
• BCL-2 family: regulators of cell death [7].
• BCL-2 can rescue maturation at several points of lymphocyte development [7].

Chemical compound and disease context of BCL2

• Decreased C-MYC and BCL2 expression correlates with methylprednisolone-mediated inhibition of Raji lymphoma growth [8].
• Here, we asked whether alterations in the p53 and RB pathways and the expression of six BCL-2 family proteins predicted acute cytotoxicity and clonogenic cell death induced by BCNU, vincristine, cytarabine, teniposide, doxorubicin, camptothecin or beta-lapachone in 12 human malignant glioma cell lines [9].
• Gemcitabine cytotoxicity of human malignant glioma cells: modulation by antioxidants, BCL-2 and dexamethasone [10].
• Down regulation of bcl2 expression in invasive ductal carcinomas is both estrogen- and progesterone-receptor dependent and associated with poor prognostic factors [11].
• It was found that the proposed liposomal delivery system successfully delivered ASOs and DOX to cell nuclei, inhibited MRP1 and BCL2 protein synthesis, and substantially increased the anticancer action of DOX by stimulating the caspase-dependent pathway of apoptosis in multidrug-resistant human lung cancer cells [12].

Biological context of BCL2

• Disruption of Mitf in melanocytes or melanoma triggered profound apoptosis susceptible to rescue by BCL2 overexpression [1].
• Induction of cell death required the mitochondrial pathway, as prostate-specific coexpression of BCL2 blocked apoptosis [13].
• The translocation involves the immunoglobulin (Ig) heavy-chain joining (JH) region gene on chromosome 14 and the BCL2 gene on chromosome 18, resulting in dysregulated expression of the BCL2 gene [14].
• BACKGROUND: The bcl-2 gene (also known as BCL2) encodes for a mitochondrial protein thought to prevent apoptosis of normal cells [15].
• We discuss such synergy with respect to the cooperating oncogenes MYC, RAS and BCL2 [16].

Anatomical context of BCL2

• The background frequency of t(14;18) (q32;q21) chromosomal translocations at the locus associated with B-cell leukemia/lymphoma-2 (BCL2) was determined from a survey of the peripheral blood lymphocytes (PBLs) of 53 living individuals and from tissues of 31 autopsies by using a nested PCR assay [17].
• BCL2 repression by these microRNAs induces apoptopsis in a leukemic cell line model [18].
• In a Burkitt lymphoma cell line, both types of agents likewise stimulated phosphorylation of myeloid cell leukemia 1 (MCL1), another viability-promoting BCL2 family member [19].
• BCL2 translocation defines a unique tumor subset within the germinal center B-cell-like diffuse large B-cell lymphoma [20].
• Expression of genes whose products may protect monocyte viability, such as BCL2-related protein, metallothioneins, CD71, and SOCS3, was up-regulated at 4 to 6 h and remained elevated throughout the 18-h time course [21].

Associations of BCL2 with chemical compounds

• BAD antagonizes both the cell cycle and antiapoptotic functions of BCL2 and BCL-x(L) through BH3 binding [22].
• DeltaMEK1:ER+BCL2 cells remained viable for at least 3 days after estradiol deprivation, whereas viability was readily lost upon withdrawal of beta-estradiol in the MEK1-responsive cells which lacked BCL2 overexpression [23].
• However, beta-carotene-induced expression changes of BAX and other BCL2 pathway genes did not lead to the predicted induction of apoptosis in the A375 cells [24].
• No change in BCL2 expression was found after exposure to IC(50) concentrations of flavopiridol [25].
• Multidrug resistance can be caused by the membrane-bound multidrug-resistance-associated protein, the detoxifying glutathione metabolism, the antiapoptotic protein BCL2, and changes in levels or activity of the topoisomerase enzymes [26].
• The induction of Bcl-2 inhibited apoptosis induced by serum starvation or etoposide, and PKCepsilon activation attenuated etoposide-induced caspase-3 cleavage [27].
• A total of 19 patients with the lowest levels of BCL2 protein expression were biologically and clinically heterogeneous; 5 patients exhibited high-level BCL2 RNA expression and 4 were fludarabine resistant [28].

Physical interactions of BCL2

• E1B-19K is a BCL2 homolog that binds and inactivates proapoptotic BAK and BAX [29].
• Bcl2/adenovirus EIB 19kD-interacting protein 3 (BNIP3) is a cell death factor that is a member of the Bcl-2 proapoptotic family recently shown to induce necrosis rather than apoptosis [30].
• Detailed promoter analysis and gel shift assays identified three GLI binding sites in the human BCL2 cis-regulatory region [31].
• The proapoptotic effect of BAX is negatively regulated by its binding with BCL-2 [32].
• OBJECTIVE: BAG-1 has anti-apoptotic actions and is known to bind BCL-2 and steroid receptors [33].

Enzymatic interactions of BCL2

• Expression of a series of wild-type and dominant-negative kinases indicated an ASK1/Jun N-terminal protein kinase 1 (JNK1) pathway phosphorylated BCL-2 in vivo [34].
• BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M [34].
• Hybridization studies with various DNA probes from the IGH locus as well as the BCL2 gene demonstrated that the mu-constant gene was deleted on the functional IGH allele of FL-318G cells, and that the cells produced abundant productive gamma-chain messages [35].

Regulatory relationships of BCL2

• In addition, p53 has been found to down-regulate the expression of BCL-2, which is able to block apoptosis induced by both p53-dependent and independent signaling events [36].
• Overexpression of BCL2 blocks TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells [37].
• Whereas overexpression of BCL2 abrogates the apoptotic response, Stat3-independent signals appear to downregulate expression of the BCL2 gene [38].
• Regulation of MCL1 through a serum response factor/Elk-1-mediated mechanism links expression of a viability-promoting member of the BCL2 family to the induction of hematopoietic cell differentiation [39].
• Anti-HEC antibody also induced the apoptosis of M-Mphi cultured in the presence of M-CSF and GM-Mphi and A-Mphi cultured in the presence or absence of GM-CSF and down-regulated the expression of BCL-2 and BCL-X(L) in these Mphis [40].

Other interactions of BCL2

• Survival probability depends on multiple biologic factors, including overexpression of Bcl2, p53, Bax, Bcl-X(L), MIB1, and apoptotic index [41].
• Alterations in 2p, 3q, 13, and 18q were not associated with N-MYC, BCL6, RB, or BCL2 alterations, respectively, suggesting that other genes may be the targets of these genetic abnormalities in MCLs [42].
• These and other data suggest that genes at 18q21.3, other than BCL2 and FVT1, may be targets for translocation in certain subgroups of B-NHL [4].
• Northern blotting and immunoblotting analyses revealed that the expression level of MCL1, a member of the BCL2 family, was increased by VEGF [43].
• The expression of BCL-2 was higher in M-Mphi, and M-CSF withdrawal down-regulated the expression [40].
• Deletion of any of the BH domains from Bcl2 abrogates the ability of Bcl2 to interact with APE1 as well as the inhibitory effects of Bcl2 on APE1 activity and AP site repair [44].

Analytical, diagnostic and therapeutic context of BCL2

• However, it is not known whether somatic mutations that alter BCL2 proteins occur in vivo or whether they result from chemotherapy or arise through other mechanisms [3].
• The presence of BCL2 rearrangements did not significantly affect overall survival (OS) or disease-free survival (DFS) [45].
• To elucidate the molecular mechanisms underlying this inhibitory effect of VEGF, we examined expression levels of BCL2 family proteins in CMK86, a human leukemia cell line, after treatment with VEGF [43].
• Quantitative flow cytometry for BCL2 and MYC expression showed abundant expression of both proteins in all three lines [46].
• As demonstrated by Southern blot analysis, BCL2 at 18q21, but not MLL/ALL1 at 11q23, was involved in these translocations [47].

References