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Bcl2  -  B cell leukemia/lymphoma 2

Mus musculus

Synonyms: AW986256, Apoptosis regulator Bcl-2, Bcl-2, C430015F12Rik, D630044D05Rik, ...
 
 
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Disease relevance of Bcl2

 

Psychiatry related information on Bcl2

  • Central component of the machinery of apoptosis program in neurons of patients with Alzheimer's disease includes proteins of caspases and Bcl-2 families [5].
  • And Bcl-2, amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors, and inositol homeostasis represent important pharmacological targets for mood stabilizers, but additional behavioral research is needed to more fully delineate their behavioral effects [6].
  • Sequential activation of individual caspases, and of alterations in Bcl-2 proapoptotic signals in a mouse model of Huntington's disease [7].
  • Increased anxiety-like behaviors and mitochondrial dysfunction in mice with targeted mutation of the Bcl-2 gene: further support for the involvement of mitochondrial function in anxiety disorders [8].
  • We found that water deprivation leads to simultaneous activation of synthesis of VP and p53 and Bcl-2 apoptotic proteins in the mouse brain [9].
 

High impact information on Bcl2

 

Chemical compound and disease context of Bcl2

 

Biological context of Bcl2

  • Here, we review the details of the apoptotic machinery as revealed by mice deficient in critical components of cell-death pathways; we concentrate on cell-death regulators classified as members of the caspase and Bcl2 families or, broadly, as adaptors and mitochondrial released factors [16].
  • Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability [1].
  • Moreover, tumors harboring a Bcl2-mediated apoptotic block undergo a drug-induced cytostasis involving the accumulation of p53, p16(INK4a), and senescence markers, and typically acquire p53 or INK4a mutations upon progression to a terminal stage [17].
  • B cell-specific transgenic expression of Bcl2 rescues early B lymphopoiesis but not B cell responses in BOB.1/OBF.1-deficient mice [18].
  • Cyclin D1-induced apoptosis, like neuronal apoptosis, can be inhibited by 21 kDa E1B, Bcl2 and pRb, but not by 55 kDa E1B [19].
 

Anatomical context of Bcl2

  • In contrast, mice deficient for Bcl2 show a relative increase in MZ B cell numbers, indicating a previously undetected function of Bcl2 for this B cell compartment [18].
  • The critical role played by the intracellular balance, probably hormonally controlled, of the BclxL and Bax proteins (Bcl2 is apparently not expressed in normal mouse testis) in this early apoptotic wave is shown by the occurrence of a comparable testicular syndrome in mice defective in the bax gene [2].
  • Bcl2 phosphorylation at Ser-70 may be required for the full and potent suppression of apoptosis in IL-3-dependent myeloid cells and can result from agonist activation of mitochondrial protein kinase C (PKC) [20].
  • The peripheral T-cell compartment was larger in the VavP-Bcl2 mice than in E mu-Bcl2 strains and, notably, CD4 T cells were 5-fold increased over normal [4].
  • Bcl2 is functionally expressed in mitochondria where it can act as an antioxidant that may regulate intracellular reactive oxygen species (ROS) [21].
 

Associations of Bcl2 with chemical compounds

  • Recently, we discovered that Bcl2 is phosphorylated at an evolutionarily conserved serine residue (Ser70) after treatment with the survival agonists IL-3 or bryostatin 1, a potent activator of protein kinase (Ito, T., Deng, X., Carr, B., and May, W [22].
  • Treatment with AGN194204 and 9-cis-retinoic acid significantly decreased apoptosis measured by annexin V staining but did not affect expression of Bcl2 and Bcl-xL [23].
  • Dominant-negative (DN)-JNK1 can block both anisomycin and latent IL-3 withdrawal-induced Bcl2 phosphorylation (>90%) and potently enhances cell death [24].
  • Diazoxide increased the levels of Bcl2 and inhibited the association of Bax with mitochondria in neurons exposed to an apoptotic insult, suggesting that activation of mitochondrial ATP-sensitive potassium channels may stabilize mitochondrial function by differentially modulating proapoptotic and antiapoptotic proteins [25].
  • Bcl2 mRNA expression was low in most of the dietary treatment groups compared with positive (estradiol implant) controls [26].
 

Physical interactions of Bcl2

  • The BH3-only proteins Bim and Bad bind to the antiapoptotic Bcl-2 proteins and induce apoptosis in wild-type cells and cells from either bax(-/-) or bak(-/-) animals [27].
  • Taken together, these results provide unprecedented evidence that the membrane-associated anti-apoptotic CD19-Lyn complex may be at least as important as Bcl-2/Bax ratio for survival of lymphoma cells [28].
  • Blk contains a conserved BH3 domain and can interact with the anti-apoptotic proteins Bcl-2 and Bcl-xL [29].
  • Bag-1 is a heat shock 70 kDa (Hsp70)-binding protein that can collaborate with Bcl-2 in suppressing apoptosis under some conditions [30].
  • Proapoptotic activity of ITM2B(s), a BH3-only protein induced upon IL-2-deprivation which interacts with Bcl-2 [31].
 

Enzymatic interactions of Bcl2

  • Furthermore, the apoptotic rate of SAC-treated tumours increased together with a decrease in Bcl-2 and increase in cleaved caspase-3 [32].
 

Regulatory relationships of Bcl2

  • The susceptibility of a cell to a death signal is determined by these competing dimerizations in which levels of Bad influence the effectiveness of Bcl-2 versus Bcl-xL in repressing death [33].
  • BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak [27].
  • Reportedly, antiapoptotic Bcl-2 family proteins suppress apoptosis by binding to and inhibiting members of the CED-4 family of caspase activators [34].
  • We analyzed several knockout and transgenic mouse lines and found that T cell receptor/CD3-ligation-induced killing of semimature thymocytes occurred independently of Fas and "death receptor" signaling in general but required the proapoptotic BH3-only protein Bim and could be inhibited by Bcl-2 [35].
  • These findings provide the first evidence that a proapoptotic Bcl-2 family protein induces apoptosis exclusively via Bak [36].
 

Other interactions of Bcl2

  • In the hematopoietic cell line BAF-B03, the expression of any two of lckF505 (an active form of p56lck), Bcl-2, or c-Myc is sufficient to promote transit of the cell cycle, regardless of the activation state of the third pathway [37].
  • Both yeast two-hybrid screening and lambda expression cloning identified a novel interacting protein, Bad, whose homology to Bcl-2 is limited to the BH1 and BH2 domains [33].
  • Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice [38].
  • Tumor-cell resistance to death receptor--induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax [39].
  • Our results suggest a different, broader role, because Bcl-2 overexpression increased lymphocyte numbers in mice and inhibited many apoptotic stimuli, but the absence of Apaf-1 or caspase-9 did not [40].
 

Analytical, diagnostic and therapeutic context of Bcl2

References

  1. Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. McGill, G.G., Horstmann, M., Widlund, H.R., Du, J., Motyckova, G., Nishimura, E.K., Lin, Y.L., Ramaswamy, S., Avery, W., Ding, H.F., Jordan, S.A., Jackson, I.J., Korsmeyer, S.J., Golub, T.R., Fisher, D.E. Cell (2002) [Pubmed]
  2. An early and massive wave of germinal cell apoptosis is required for the development of functional spermatogenesis. Rodriguez, I., Ody, C., Araki, K., Garcia, I., Vassalli, P. EMBO J. (1997) [Pubmed]
  3. Bim is a suppressor of Myc-induced mouse B cell leukemia. Egle, A., Harris, A.W., Bouillet, P., Cory, S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  4. VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia. Egle, A., Harris, A.W., Bath, M.L., O'Reilly, L., Cory, S. Blood (2004) [Pubmed]
  5. Differential expression of proteins of caspases and Bcl-2 families in the brain of mice. Min, S.H., Hwang, D.Y., Kang, T.S., Hwang, J.H., Lim, C.H., Lee, S.H., Lim, H.J., Seo, S.J., Sheen, Y.Y., Paik, S.G., Cho, J.S., Kim, Y.K. Int. J. Mol. Med. (2003) [Pubmed]
  6. Cellular plasticity cascades: genes-to-behavior pathways in animal models of bipolar disorder. Einat, H., Manji, H.K. Biol. Psychiatry (2006) [Pubmed]
  7. Sequential activation of individual caspases, and of alterations in Bcl-2 proapoptotic signals in a mouse model of Huntington's disease. Zhang, Y., Ona, V.O., Li, M., Drozda, M., Dubois-Dauphin, M., Przedborski, S., Ferrante, R.J., Friedlander, R.M. J. Neurochem. (2003) [Pubmed]
  8. Increased anxiety-like behaviors and mitochondrial dysfunction in mice with targeted mutation of the Bcl-2 gene: further support for the involvement of mitochondrial function in anxiety disorders. Einat, H., Yuan, P., Manji, H.K. Behav. Brain Res. (2005) [Pubmed]
  9. Apoptotic signaling proteins: possible participation in the regulation of vasopressin and catecholamines biosynthesis in the hypothalamus. Chernigovskaya, E.V., Taranukhin, A.G., Glazova, M.V., Yamova, L.A., Fedorov, L.M. Histochem. Cell Biol. (2005) [Pubmed]
  10. Regulation of lymphocyte survival by the bcl-2 gene family. Cory, S. Annu. Rev. Immunol. (1995) [Pubmed]
  11. Proapoptotic BH3-only Bcl-2 family member Bik/Blk/Nbk is expressed in hemopoietic and endothelial cells but is redundant for their programmed death. Coultas, L., Bouillet, P., Stanley, E.G., Brodnicki, T.C., Adams, J.M., Strasser, A. Mol. Cell. Biol. (2004) [Pubmed]
  12. Endogenously produced ganglioside GM3 endows etoposide and doxorubicin resistance by up-regulating Bcl-2 expression in 3LL Lewis lung carcinoma cells. Noguchi, M., Kabayama, K., Uemura, S., Kang, B.W., Saito, M., Igarashi, Y., Inokuchi, J. Glycobiology (2006) [Pubmed]
  13. Bcl-2 inhibits gut epithelial apoptosis induced by acute lung injury in mice but has no effect on survival. Husain, K.D., Stromberg, P.E., Javadi, P., Buchman, T.G., Karl, I.E., Hotchkiss, R.S., Coopersmith, C.M. Shock (2003) [Pubmed]
  14. The effect of Bcl-2 adenovirus against murine hepatocyte apoptosis caused by tumor necrosis factor alpha and D-galactosamine. Zhang, B., Zhang, D., Ren, H., Ma, Y. Zhonghua Gan Zang Bing Za Zhi (2001) [Pubmed]
  15. Characterization of Apt- cell lines exhibiting cross-resistance to glucocorticoid- and Fas-mediated apoptosis. Askew, D.J., Kuscuoglu, U., Brunner, T., Green, D.R., Miesfeld, R.L. Cell Death Differ. (1999) [Pubmed]
  16. Mouse models of cell death. Ranger, A.M., Malynn, B.A., Korsmeyer, S.J. Nat. Genet. (2001) [Pubmed]
  17. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Schmitt, C.A., Fridman, J.S., Yang, M., Lee, S., Baranov, E., Hoffman, R.M., Lowe, S.W. Cell (2002) [Pubmed]
  18. B cell-specific transgenic expression of Bcl2 rescues early B lymphopoiesis but not B cell responses in BOB.1/OBF.1-deficient mice. Brunner, C., Marinkovic, D., Klein, J., Samardzic, T., Nitschke, L., Wirth, T. J. Exp. Med. (2003) [Pubmed]
  19. Cyclin D1 is an essential mediator of apoptotic neuronal cell death. Kranenburg, O., van der Eb, A.J., Zantema, A. EMBO J. (1996) [Pubmed]
  20. Survival function of ERK1/2 as IL-3-activated, staurosporine-resistant Bcl2 kinases. Deng, X., Ruvolo, P., Carr, B., May, W.S. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  21. Bcl2 retards G1/S cell cycle transition by regulating intracellular ROS. Deng, X., Gao, F., May, W.S. Blood (2003) [Pubmed]
  22. Reversible phosphorylation of Bcl2 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A. Deng, X., Ito, T., Carr, B., Mumby, M., May, W.S. J. Biol. Chem. (1998) [Pubmed]
  23. Retinoid x receptor agonists increase bcl2a1 expression and decrease apoptosis of naive T lymphocytes. Rasooly, R., Schuster, G.U., Gregg, J.P., Xiao, J.H., Chandraratna, R.A., Stephensen, C.B. J. Immunol. (2005) [Pubmed]
  24. Novel role for JNK as a stress-activated Bcl2 kinase. Deng, X., Xiao, L., Lang, W., Gao, F., Ruvolo, P., May, W.S. J. Biol. Chem. (2001) [Pubmed]
  25. Activation of mitochondrial ATP-dependent potassium channels protects neurons against ischemia-induced death by a mechanism involving suppression of Bax translocation and cytochrome c release. Liu, D., Lu, C., Wan, R., Auyeung, W.W., Mattson, M.P. J. Cereb. Blood Flow Metab. (2002) [Pubmed]
  26. Soy processing influences growth of estrogen-dependent breast cancer tumors. Allred, C.D., Allred, K.F., Ju, Y.H., Goeppinger, T.S., Doerge, D.R., Helferich, W.G. Carcinogenesis (2004) [Pubmed]
  27. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Zong, W.X., Lindsten, T., Ross, A.J., MacGregor, G.R., Thompson, C.B. Genes Dev. (2001) [Pubmed]
  28. Membrane-associated CD19-LYN complex is an endogenous p53-independent and Bc1-2-independent regulator of apoptosis in human B-lineage lymphoma cells. Myers, D.E., Jun, X., Waddick, K.G., Forsyth, C., Chelstrom, L.M., Gunther, R.L., Tumer, N.E., Bolen, J., Uckun, F.M. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  29. Blk, a BH3-containing mouse protein that interacts with Bcl-2 and Bcl-xL, is a potent death agonist. Hegde, R., Srinivasula, S.M., Ahmad, M., Fernandes-Alnemri, T., Alnemri, E.S. J. Biol. Chem. (1998) [Pubmed]
  30. Bag-1 and Bcl-2 gene transfer in malignant glioma: modulation of cell cycle regulation and apoptosis. Roth, W., Grimmel, C., Rieger, L., Strik, H., Takayama, S., Krajewski, S., Meyermann, R., Dichgans, J., Reed, J.C., Weller, M. Brain Pathol. (2000) [Pubmed]
  31. Proapoptotic activity of ITM2B(s), a BH3-only protein induced upon IL-2-deprivation which interacts with Bcl-2. Fleischer, A., Ayllón, V., Dumoutier, L., Renauld, J.C., Rebollo, A. Oncogene (2002) [Pubmed]
  32. S-allylcysteine, a water-soluble garlic derivative, suppresses the growth of a human androgen-independent prostate cancer xenograft, CWR22R, under in vivo conditions. Chu, Q., Lee, D.T., Tsao, S.W., Wang, X., Wong, Y.C. BJU Int. (2007) [Pubmed]
  33. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Yang, E., Zha, J., Jockel, J., Boise, L.H., Thompson, C.B., Korsmeyer, S.J. Cell (1995) [Pubmed]
  34. Apoptotic protease activating factor 1 (Apaf-1)-independent cell death suppression by Bcl-2. Haraguchi, M., Torii, S., Matsuzawa, S., Xie, Z., Kitada, S., Krajewski, S., Yoshida, H., Mak, T.W., Reed, J.C. J. Exp. Med. (2000) [Pubmed]
  35. Negative selection of semimature CD4(+)8(-)HSA+ thymocytes requires the BH3-only protein Bim but is independent of death receptor signaling. Villunger, A., Marsden, V.S., Zhan, Y., Erlacher, M., Lew, A.M., Bouillet, P., Berzins, S., Godfrey, D.I., Heath, W.R., Strasser, A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  36. Bak but not Bax is essential for Bcl-xS-induced apoptosis. Lindenboim, L., Kringel, S., Braun, T., Borner, C., Stein, R. Cell Death Differ. (2005) [Pubmed]
  37. Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation. Miyazaki, T., Liu, Z.J., Kawahara, A., Minami, Y., Yamada, K., Tsujimoto, Y., Barsoumian, E.L., Permutter, R.M., Taniguchi, T. Cell (1995) [Pubmed]
  38. Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice. Akashi, K., Kondo, M., von Freeden-Jeffry, U., Murray, R., Weissman, I.L. Cell (1997) [Pubmed]
  39. Tumor-cell resistance to death receptor--induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax. LeBlanc, H., Lawrence, D., Varfolomeev, E., Totpal, K., Morlan, J., Schow, P., Fong, S., Schwall, R., Sinicropi, D., Ashkenazi, A. Nat. Med. (2002) [Pubmed]
  40. Apoptosis initiated by Bcl-2-regulated caspase activation independently of the cytochrome c/Apaf-1/caspase-9 apoptosome. Marsden, V.S., O'Connor, L., O'Reilly, L.A., Silke, J., Metcalf, D., Ekert, P.G., Huang, D.C., Cecconi, F., Kuida, K., Tomaselli, K.J., Roy, S., Nicholson, D.W., Vaux, D.L., Bouillet, P., Adams, J.M., Strasser, A. Nature (2002) [Pubmed]
  41. Expression of apoptosis regulatory proteins in tubular epithelium stressed in culture or following acute renal failure. Ortiz, A., Lorz, C., Catalán, M.P., Danoff, T.M., Yamasaki, Y., Egido, J., Neilson, E.G. Kidney Int. (2000) [Pubmed]
  42. A murine ortholog of the human serpin SCCA2 maps to chromosome 1 and inhibits chymotrypsin-like serine proteinases. Bartuski, A.J., Kamachi, Y., Schick, C., Massa, H., Trask, B.J., Silverman, G.A. Genomics (1998) [Pubmed]
  43. Maspin overexpression modulates tumor cell apoptosis through the regulation of Bcl-2 family proteins. Zhang, W., Shi, H.Y., Zhang, M. BMC Cancer (2005) [Pubmed]
  44. Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Hotchkiss, R.S., Chang, K.C., Swanson, P.E., Tinsley, K.W., Hui, J.J., Klender, P., Xanthoudakis, S., Roy, S., Black, C., Grimm, E., Aspiotis, R., Han, Y., Nicholson, D.W., Karl, I.E. Nat. Immunol. (2000) [Pubmed]
  45. Bcl-XL and Bcl-2 repress a common pathway of cell death. Chao, D.T., Linette, G.P., Boise, L.H., White, L.S., Thompson, C.B., Korsmeyer, S.J. J. Exp. Med. (1995) [Pubmed]
 
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