Disease relevance of Bcl2l1

• Selective regulation of Bcl-XL by a Jak kinase-dependent pathway is bypassed in murine hematopoietic malignancies [1].
• Bcl-XL disrupts death-inducing signal complex formation in plasma membrane induced by hypoxia/reoxygenation [2].
• METHODS: Hepatocytes isolated from mice homozygous for a floxed bcl-x allele (bcl-x fl/fl) were infected with recombinant adenovirus expressing the Cre recombinase gene (AdexCre) [3].
• Mice with conditional knockout of Bcl-x(L) (conditional bcl-x(-/-) mice) develop severe anemia that has been attributed to hemolysis and is accompanied by splenomegaly [4].
• Bcl-XL is required for heme synthesis during the chemical induction of erythroid differentiation of murine erythroleukemia cells independently of its antiapoptotic function [5].

High impact information on Bcl2l1

• Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death [6].
• TCR ligation upregulated Bim expression and promoted interaction of Bim with Bcl-XL, inhibiting its survival function [7].
• bcl-x is a member of the bcl-2 gene family, which may regulate programmed cell death [8].
• Analyses of bcl-x double-knockout chimeric mice showed that the maturation of Bcl-x-deficient lymphocytes was diminished [8].
• These findings are the first to show that Rel/NF-kappaB regulates physiologically the expression of a Bcl-2-like protein that is critical for the control of cell survival during lymphocyte activation [9].

Chemical compound and disease context of Bcl2l1

• These data suggest that the responsiveness of ovarian cancer to paclitaxel and cisplatin in vivo, and therefore perhaps clinically, is influenced by levels of the antiapoptotic protein BclXL [10].

Biological context of Bcl2l1

• Finally, overexpression of Bcl-XL effectively protected IL-3-dependent myeloid cells from apoptosis following removal of trophic factors [1].
• Tumors harboring bcl-X insertions had altered bcl-X RNAs, expressed elevated levels of Bcl-XL protein, and lacked the requirements for cytokines normally essential for cell survival [1].
• Therefore, Bcl-XL functions as a key cytokine regulated anti-apoptotic protein in myelopoiesis and contributes to leukemia cell survival [1].
• To assess the role of Bcl-xL in thymocyte apoptosis, we generated mice overexpressing an E mu-bcl-x transgene within the T cell compartment [11].
• The results demonstrated IL-3-independent growth by Ik6-transfected 32D clones coincident with up-regulation of the antiapoptotic protein Bcl-XL [12].

Anatomical context of Bcl2l1

• p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the endoplasmic reticulum [13].
• In contrast, caspase-3, but not bcl-x, deficiency changed the normal incidence of neuronal progenitor cell apoptosis, consistent with the lack of expression of Bcl-X(L) in the proliferative population of the embryonic cortex [14].
• These alterations result in mild uncoupling of mitochondrial state-4 respiration, associated with an inhibition the adenosine diphosphate (ADP)-stimulated respiration and phosphorylation rate. tBid disruption of mitochondrial homeostasis was inhibited in mitochondria overexpressing Bcl-2 and Bcl-XL [15].
• In contrast, decreased apoptosis was observed in specific locations that suffered from developmental deficits, indicating that proapoptotic isoform(s) produced from Bcl2l might have roles in inner ear development [16].
• In Apaf1(-/-)/Bcl2l(-/-) double mutant embryos, no cell death could be detected in the otic epithelium, demonstrating that the cell death regulated by the anti-apoptotic Bcl2l isoform, Bcl-X(L) in the otic epithelium is Apaf1-dependent [16].

Associations of Bcl2l1 with chemical compounds

• These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells [17].
• p21Cip1 protection against hyperoxia requires Bcl-XL and is uncoupled from its ability to suppress growth [18].
• Oxidized low density lipoprotein inhibits macrophage apoptosis by blocking ceramide generation, thereby maintaining protein kinase B activation and Bcl-XL levels [19].
• Here we demonstrate that expression of Bax, a Bcl-2-like protein, is increased at the blastocyst stage in the presence of high concentrations of glucose, and that these changes correlate morphologically with increased DNA fragmentation [20].
• The PT pore complex is regulated by thiol-reactive agents, calcium, cyclophilin D ligands (cyclosporin A and a nonimmunosuppressive cyclosporin A derivative), ligands of the adenine nucleotide translocator, apoptosis-related endoproteases (caspases), and Bcl-2-like proteins [21].

Physical interactions of Bcl2l1

• N-Bak interacts with Bcl-XL but not BAX, suggesting an indirect mechanism for promoting Bax translocation to the mitochondria [22].
• Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL [23].
• Electrophoretic mobility shift assay suggested differences in binding of the NF-kappaB complexes to these putative NF-kappaB binding sites of the bcl-x gene [24].

Enzymatic interactions of Bcl2l1

• We found that Bcl-XL protein was cleaved by caspase-3/CPP32 at two sites in the loop domain (i.e., HLAD61/S and SSLD76/A) [25].
• However, Bax with BH3 deleted did not form heterodimers with Bcl-XL, but retained its ability to counter the death repressor activity of Bcl-XL [26].

Regulatory relationships of Bcl2l1

• c-Myc augments gamma irradiation-induced apoptosis by suppressing Bcl-XL [27].
• Overexpression of Bad in murine FL5.12 cells demonstrated that the protein not only could abrogate the protective capacity of coexpressed Bcl-XL but could accelerate the apoptotic response to a death signal when it was expressed in the absence of exogenous Bcl-XL [28].
• In this report, we examine whether Stat5 can induce transactivation of the bcl-x gene in response to Epo [29].
• We now demonstrate that BTK regulates bcl-x expression by transcriptional control in response to BCR engagement [30].
• Stable transfection of either bcl-2 or bcl-x expression plasmids promotes the survival of CTLL-2 cells in the setting of IL-2 withdrawal [31].

Other interactions of Bcl2l1

• Bcl-XL and Bcl-2 repress a common pathway of cell death [32].
• Among the Bcl-2 family proteins only Bid and Bcl-XL continue to be expressed at high levels in the adult brain [33].
• Together, these results demonstrate that PU.1 and Ets2 dramatically increase bcl-x activation, which is necessary for the cytocidal function and survival of macrophages [34].
• Bruton's tyrosine kinase targets NF-kappaB to the bcl-x promoter via a mechanism involving phospholipase C-gamma2 following B cell antigen receptor engagement [30].
• Molecular linkage analysis using interspecific backcross mice revealed the murine Bcl2l locus at 0.7 cM terminal to D2Mit22, and the murine Bax locus at 0.8 cM terminal to D7Nds5 [35].

Analytical, diagnostic and therapeutic context of Bcl2l1

• Elimination of Bclx by gene targeting dramatically shortens the survival of DP thymocytes but not the survival of SP thymocytes or peripheral SP T cells [36].
• Immunoblotting analysis showed no upregulation of pro-apoptotic proteins (caspase-2L, -3, -6, -8, -9, and Bax) with age while all the anti-apoptotic proteins (caspase-2S, Bcl-2, and Bcl-XL) remained unchanged during aging [37].
• The bcl-xS splice variant of bcl-x can promote cell death, and bcl-xL has a protective function in cell culture [38].
• The drug effects on the expression of the beta-tubulin isotypes, Bcl-2, Bax, Bcl-XL and proteomic profiles were evaluated by immunobloting and SELDI mass spectrometry in tumor xenografts dosed at 0.5 MTDs [39].
• Western blot analysis revealed decreased phosphorylation levels of STAT-5 and reduced expression of Bcl-XL in RGCs of axotomized tg21 animals, suggesting that the corresponding pathways are not crucial for Epo's neuroprotective activity [40].

References