Skip to main content
SpringerLink
Log in

Structure—Function Analysis of Bcl-2 Family Proteins

Regulators of Programmed Cell Death

  • Chapter
Book cover Mechanisms of Lymphocyte Activation and Immune Regulation VI

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 406))

Abstract

The Bcl-2 protein blocks a distal step in an evolutionarily conserved pathway for programmed cell death and apoptosis. To gain better understanding of how this protein functions, we have undertaken a structure-function analysis of this protein, focusing on domains within Bcl-2 that are required for function and for interactions with other proteins. Four conserved domains are present in Bcl-2 and several of its homologs: BH1 (residues 136–155), BH2 (187–202), BH3 (93–107) and BH4 (10–30). Deletion of the BH1, BH2, or BH4 domains of Bcl-2 abolishes its ability to suppress cell death in mammalian cells and prevents homodimerization of these mutant proteins, though these mutants can still bind to the wild-type Bcl-2 protein. These mutants also fail to bind to BAG-1 and Raf-1, two proteins that we have shown can associate with protein complexes containing Bcl-2 and which cooperate with Bcl-2 to suppress cell death. Deletion of either BH1 or BH2 nullifies the ability of Bcl-2 to: (a) suppress death in mammalian cells; (b) block Bax-induced lethality in yeast; and (c) heterodimerize with Bax. In contrast, deletion of the BH4 domain of Bcl-2 nullifies anti-apoptotic function and homodimerization, but does not impair binding to the pro-apoptotic protein Bax. Taken together, the data suggest the possibility that both Bcl-2/Bcl-2 homodimerization and Bcl-2/Bax heterodimerization are necessary but insufficient for the anti-apoptotic function of the Bcl-2 protein. Homodimerization of Bcl-2 with itself involves a head-to-tail interaction, in which an N-terminal domain where BH4 resides interacts with the more distal region of Bcl-2 where BH1, BH2, and BH3 are located. In contrast, Bcl-2/Bax heterodimerization involves a tail-to-tail interaction, that requires the portion of Bcl-2 where BH1, BH2, and BH3 reside and a central region in Bax where the BH3 domain is located. The BH3 domain of Bax is also required for Bax/Bax homodimerization and pro-apoptotic function in both yeast and mammalian cells. Thus, Bcl-2 may suppress cell death at least in part by binding to Bax via the BH3 domain and thereby preventing formation of Bax/Bax homodimers. Further studies however are required to delineate the full significance of Bcl-2/Bcl-2, Bcl-2/Bax, and Bax/Bax dimers and the biochemical mechanisms by which Bcl-2 family proteins ultimately control cell life and death.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. G.H. Fisher, F.J. Rosenberg, S.E. Straus, J.K. Dale, L.A. Middelton, A.Y. Lin, W. Strober, M.J. Lenardo and J.M. Puck, Dominant interfering fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome, Cell 81: 935 (1995).

    Article  PubMed  CAS  Google Scholar 

  2. J.P. DiSanto, J.Y. Bonnefoy, J.F. Gauchat, A. Fischer and G. de Saint Basile, CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM, Nature 361: 541 (1993).

    Article  PubMed  CAS  Google Scholar 

  3. R.C. Allen, R.J. Armitage, M.E. Conley, H. Rosenblatt, N.A. Jenkins, N.G. Copeland, M.A. Bedell, S. Edelhoff, C.M. Disteche, D.K. Simoneaux, W.C. Fanslow, J. Belmont and M.K. Spriggs, CD40 ligand gene defects responsble for X-linked hyper-IgM syndrome, Science 259: 990 (1993).

    Article  PubMed  CAS  Google Scholar 

  4. M.O. Westendorp, R. Frank, C. Ochsenbauer, K. Stricker, J. Dhein, H. Waleczak, K.-M. Debatin and P.H. Krammer, Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp 120, Nature 375: 497 (1995).

    Article  PubMed  CAS  Google Scholar 

  5. T.H. Finkel and N.K. Banda, Indirect mechanisms of HIV pathogenesis: how does HIV kill T cells? Curr. Opin. Immun. 6: 605 (1994).

    Article  CAS  Google Scholar 

  6. L. Meyaard, S.A. Otto, R.R. Jonker, M.J. Mijnster, R.P. Keet and F. Miedema, Programmed death of T cells in HIV-1 infection, Science 257: 217 (1992).

    Article  PubMed  CAS  Google Scholar 

  7. M.L. Gougeon, S. Garcia, J. Heeney, R. Tschopp, H. Lecoeur, D. Guetard, V. Rame, C. Dauguet and L. Montagnier, Programmed cell death in AIDS-related HIV and SIV infections, AIDS Res. Hum. Retroviruses 9: 553 (1993).

    Article  PubMed  CAS  Google Scholar 

  8. G.T. Williams, Programmed cell death: apoptosis and oncogenesis, Cell 65: 1097 (1991).

    Article  PubMed  CAS  Google Scholar 

  9. J.C. Reed, Bcl-2 and the regulation of programmed cell death, J. Cell Biol. 124: 1 (1994).

    Article  PubMed  CAS  Google Scholar 

  10. S.J. Korsmeyer, Bcl-2 initiates a new category of oncogenes: regulators of cell death, Blood 80: 879 (1992).

    PubMed  CAS  Google Scholar 

  11. D.L. Vaux, Toward an understanding of the molecular mechansisms of physiological cell death, Proc. Natl. Acad. Sci. USA 90: 786 (1993).

    Article  PubMed  CAS  Google Scholar 

  12. Y. Tsujimoto, J. Cossman, E. Jaffe and C. Croce, Involvement of the Bcl-2 gene in human follicular lymphoma, Science 228: 1440 (1985).

    Article  PubMed  CAS  Google Scholar 

  13. Y. Tsujimoto and C.M. Croce, Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma, Proc. Natl. Acad. Sci. USA 83: 5214 (1986).

    Article  PubMed  CAS  Google Scholar 

  14. D.L. Vaux, S. Cory and J.M. Adams, Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells, Nature 335: 440 (1988).

    Article  PubMed  CAS  Google Scholar 

  15. D.M. Hockenbery, G. Nunez, C. Milliman, R.D. Schreiber and S.J. Korsmeyer, Bcl-2 is an inner mitochondria] membrane protein that blocks programmed cell death, Nature 348: 334 (1990).

    Article  PubMed  CAS  Google Scholar 

  16. J. Reed, S. Haldar, M. Cuddy, C. Croce and D. Makover, Bcl-2-mediated tumorigenicity in a T-lymphoid cell line: Synergy with C-MYC and inhibition by Bcl-2 antisense, Proc. Natl. Acad. Sci. USA 87: 3660 (1990).

    Article  PubMed  CAS  Google Scholar 

  17. J. Reed, C. Stein, S. Haldar, C. Subasinghe, C. Croce, S. Yum and J. Cohen, Antisense-mediated inhibition of Bcl-2 proto-oncogene expression and leukemic cell growth: Comparisons of phosphodiester and phosphorothioate oligodeoxynucleotides, Cancer Res. 50: 6565 (1990).

    PubMed  CAS  Google Scholar 

  18. D.A.G. Galton and I.C.M. MacLennan, Clinical patterns of B cell malignancy, Clin. Hematol. 11: 561 (1982).

    CAS  Google Scholar 

  19. Horning SJ and Rosenberg SA, The natural history of initially untreated low-grade non-Hodgkin’s lymphomas, N. Eng. J. Med. 311: 1471 (1984).

    Article  CAS  Google Scholar 

  20. M. Hanada, D. Delia, A. Aiello, E. Stadtmauer and J.C. Reed, Bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia, Blood 82: 1820 (1993).

    PubMed  CAS  Google Scholar 

  21. L. Campos, J.-P. Roualult, O. Sabido, N. Roubi, C. Vasselon, E. Archimbaud, J.-P. Magaud and D. Guyotat, High expression of Bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy, Blood 81: 3091 (1993).

    PubMed  CAS  Google Scholar 

  22. D. Campana, E. Coustan-Smith, A. Manabe, M. Buschle, S.C. Raimondi, F.G. Behm, R. Ashmun, M. Arid’, A. Biondi and C.-H. Pui, Prolonged survival of B-lineage acute lymphoblastic leukemia cells is accompanied by overexpression of Bcl-2 protein, Blood 81: 1025 (1993).

    PubMed  CAS  Google Scholar 

  23. F. Pezzella, A.G.D. Tse, J.L. Cordell, K.A.F. Pulford, K.C. Gatter and D.Y. Mason, Expression of the Bcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation, Am. J. Pathol. 137: 225 (1990).

    PubMed  CAS  Google Scholar 

  24. J.C. Reed, Bcl-2: Prevention of apoptosis as a mechanism of drug resistance, Hematology/Oncology Clinics of North America 9: 451 (1995).

    PubMed  CAS  Google Scholar 

  25. O. Hermine, C. Haioun, E. Lepage, M.-F. d’Agay, J. Briere, C. Lavignac, G. Fillet, G. Salles, J.-P. Marolleau, J. Diebold, F. Reyes and P. Gaulard, Prognostic significance of Bcl-2 protein expression in aggressive non-Hodgkin’s Lymphoma, Blood 87: 265 (1996).

    PubMed  CAS  Google Scholar 

  26. K.-I. Nakayama, K. Nakayama, I. Negishi, K. Kuida, Y. Shinkai, M.C. Louie, L.E. Fields, P.J. Lucas, V. Stewart, F.W. Alt and D.Y. Loh, Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice, Science 261: 1584 (1993).

    Article  PubMed  CAS  Google Scholar 

  27. D.J. Veis, C.M. Sorenson, J.R. Shutter and S.J. Korsmeyer, Bel-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair, Cell 75: 229 (1993).

    Article  PubMed  CAS  Google Scholar 

  28. A.N. Akbar, N. Borthwick, M. Salmon, W. Gombert, M. Bofill, N. Shamsadeen, D. Pilling, S. Pett, J.e. Grundy and G. Janossy, The significance of low bcl-2 expression by CD45RO T cells in normal individuals and patients with acute viral infections. The role of apoptosis in T cell memory, J. Exp. Med. 178: 427 (1993).

    Article  PubMed  CAS  Google Scholar 

  29. F. Boudet, H. Lecoeur and M.-L. Gougeon, Apoptosis associated with ex vivo down-regulation of Bcl-2 and up-regulation of Fas in potential cytotoxic CDS+ T lymphocytes during HIV infection, J. Immunol. in press (1995).

    Google Scholar 

  30. K.M. Kozopas, T. Yang, H.L. Buchan, P. Zhou and R. Craig, Mcl-1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to bcl-2, Proc. Natl. Acad. Sci. USA 90: 3516 (1993).

    Article  PubMed  CAS  Google Scholar 

  31. J.E. Reynolds, T. Yang, L. Qian, J.D. Jenkinson, P. Zhou, A. Eastman and R.W. Craig, Mc1–1, a member of the Bel-2 family, delays apoptosis induced by c-Myc overexpression in Chinese hamster ovary cells, Cancer Res. 54: 6348 (1994).

    PubMed  CAS  Google Scholar 

  32. Z. Oltvai, C. Milliman and S.J. Korsmeyer, Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death, Cell 74: 609 (1993).

    Article  PubMed  CAS  Google Scholar 

  33. L.H. Boise, M. Gonzalez-Garcia, C.E. Postema, L. Ding, T. Lindsten, L.A. Turka, X. Mao, G. Nunez and C.B. Thompson, bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death, Cell 74: 597 (1993).

    Google Scholar 

  34. E.Y. Lin, A. Orlofsky, M.S. Berger and M.B. Prystowsky, Characterization of Al, a novel hemopoieticspecific early-response gene with sequence similarity to Bcl-2, J. Immunol. 151: 1979 (1993).

    PubMed  CAS  Google Scholar 

  35. E.Y. Lin, A. Orlofsky, H.-G. Wang, J.C. Reed and M.B. Prystowsky, Al, a Bcl-2 family member prolongs cell survival and permits granulocyte differentiation, Blood 87: 983 (1996).

    PubMed  CAS  Google Scholar 

  36. S.S. Choi, I.-C. Park, J.W. Yun, Y.C. Sung, S. Hong and H. Shin, A novel Bcl-2 related gene, Bfl-1, is overexpressed in stomach cancer and preferentially expressed in bone marrow, Oncogene 11: 1693 (1995).

    Google Scholar 

  37. T. Chittenden, E.A. Harrington, R. O’Connor, C. Flemington, R.J. Lutz, G.I. Evan and B.C. Guild, Induction of apoptosis by the Bcl-2 homologue Bak, Nature 374: 733 (1995).

    Article  PubMed  CAS  Google Scholar 

  38. M.C. Kiefer, M.J. Brauer, V.C. Powers, J.J. Wu, s.R. Ubansky, L.D. Tomei and P.J. Barr, Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak, Nature 374: 736 (1995).

    Article  PubMed  CAS  Google Scholar 

  39. S.N. Farrow, J.H.M. White, I. Martinou, T. Raven, K.-T. Pun, C.J. Grinham, J.-C. Martinou and R. Brown, Cloning of a Bcl-2 homologue by interaction with adenovirus EIB 19K, Nature 374: 731 (1995).

    Article  PubMed  CAS  Google Scholar 

  40. G. Gillet, M. Guerin, A. Trembleau and G. Brun, A BcI-2-related gene is activated in avian cells transformed by the Rous sarcoma virus, EMBO J. 14: 1372 (1995).

    PubMed  CAS  Google Scholar 

  41. E. Yang, J. Zha, J. Jockel, L.H. Boise, C.B. Thompson and S.J. Korsmeyer, Bad: a heterodimeric partner for Bcl-XL and Bcl-2, displaces bax and promotes cell death, Cell 80: 285 (1995).

    Article  PubMed  CAS  Google Scholar 

  42. J.M. Boyd, G.J. Gallo, B. Elangovan, A.B. Houghton, S. Malstrom, B.J. Avery, R.G. Ebb, T. Subramanian, T. Chittenden, R.J. Lutz and G. Chinnadurai, Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins, Oncogene 11: 1921 (1995).

    Google Scholar 

  43. L. Rao, M. Debbas, R Sabbatini, D. Hockenbery, S. Korsmeyer and E. White, The adenovirus E 1 A proteins induce apoptosis, which is inhibited by the El 19-kDa and bcl-2 proteins, Proc. Natl. Acad. Sci. USA 89: 7742 (1992).

    Article  PubMed  CAS  Google Scholar 

  44. M.L. Cleary, S.D. Smith and J. Sklar, Cloning and structural analysis of cDNAs for Bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation, Cell 47: 19 (1986).

    Article  PubMed  CAS  Google Scholar 

  45. J.G. Neilan, Z. Lu, C.L. Afonso, G.F. Kutish, M.D. sussman and D.L. Rock, An African swine fever virus gene with similarity to the proto-oncogene bcl-2 and the Epstein-Barr virus gene BHRFI, J. Virol. 67: 4391 (1993).

    PubMed  CAS  Google Scholar 

  46. C.A. Smith, A novel viral homolgue of Bcl-2 and Ced-9, Trends Cell Biol. 5: 344 (1995).

    Article  PubMed  CAS  Google Scholar 

  47. M.O. Hengartner and H.R. Horvitz, C. elegans cell survival gene ced-9 encodes a functional homolog of the mammlian proto-oncogene Bcl-2, Cell 76: 665 (1994).

    Google Scholar 

  48. T. Sato, M. Hanada, S. Bodrug, S. Irie, N. Iwama, L.H. Boise, C.B. Thompson, E. Golemis, L. Fong, H.-G. Wang and J.C. Reed, Interactions among members of the Bcl-2 protein family analyzed with a yeast two-hybrid system, Proc. Natl. Acad. Sci. USA 91: 9238 (1994).

    Article  PubMed  CAS  Google Scholar 

  49. S.E. Bodrug, C. Aimé-Sempé, T. Sato, S. Krajewski, M. Hanada and J.C. Reed, Biochemical and functional comparisons of Mcl-1 and Bcl-2 proteins: evidence for a novel mechanism of regulating Bcl-2 family protein function, Cell Death Differ. 2: 173 (1995).

    PubMed  CAS  Google Scholar 

  50. T.W. Sedlak, Z.N. Oltvai, E. Yang, K. Wang, L.H. Boise, C.B. Thompson and S.J. Korsmeyer, Multiple Bcl-2 family members demonstrate selective dimerizations with Bax, Proc. Natl. Acad. Sci. USA 92: 7834 (1995).

    Article  PubMed  CAS  Google Scholar 

  51. S. Krajewski, S. Bodrug, R. Gascoyne, K. Berean, M. Krajewska and J.C. Reed, Immunohistochemical analysis of mcl-1 and Bcl-2 proteins in normal and neoplastic lymph nodes, Amer. J. Pathol. 145: 515 (1994).

    CAS  Google Scholar 

  52. S. Krajewski, M. Krajewska, A. Shabaik, H.-G. Wang, S. Irie, L. Fong and J.C. Reed, Immunohistochemical analysis of in vivo patterns of Bcl-X expression, Cancer Res. 54: 5501 (1994).

    PubMed  CAS  Google Scholar 

  53. N. Motoyama, F. Wang, K.A. Roth, H. Sawa, K. Nakayama, I. Negishi, S. Senju, Q. Zhang, S. Fujii and D.Y. Loh, Massive cell death of immature hematopoietic cells and neurons in Bcl-X-deficient mice, Science 267: 1506 (1995).

    Article  PubMed  CAS  Google Scholar 

  54. C.M. Knudson, K.S.K. Tung, W.G. Tourtellotte, G.A.J. Brown and S.J. Korsmeyer, Bax-deficient mice with lymphoid hyperplasia and male germ cell death, Science 270: 96 (1995).

    Article  PubMed  CAS  Google Scholar 

  55. S. Krajewski, S. Tanaka, S. Takayama, M.J. Schibler, W. Fenton and J.C. Reed, Investigations of the subcellular distribution of the Bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes, Cancer Res. 53: 4701 (1993).

    PubMed  CAS  Google Scholar 

  56. M.D. Jacobson, J.F. Burne, M.P. King, T. Miyashita, J.C. Reed and M.C. Raff, Apoptosis and bcl-2 protein in cells without mitochondrial DNA, Nature 361: 365 (1993).

    Article  PubMed  CAS  Google Scholar 

  57. R. Monaghan, D. Robertson, T. Andrew, S. Amos, M.J.S. Dyer, D.Y. Mason and M.F. Greaves, Ultrastructural localization of Bcl-2 protein, J. Histochem. Cytochem. 40: 1819 (1992).

    Article  PubMed  CAS  Google Scholar 

  58. R. Silvestrini, S. Veneroni, M.G. Daidone, E. Benini, R. Boracchi, M. Mezzetti, G. Di Fronzo, F. Rilke and U. Veronesi, The bcl-2 protein: a prognostic indicator strongly related to p53 protein in lymph node-negative breast cancer patients, J. Natl. Cancer Inst. 86: 499 (1994).

    Article  PubMed  CAS  Google Scholar 

  59. T. Yang, K.M. Kozopas and R.W. Craig, The intracellular distribution and pattern of expression of Mcl-1 overlap with, but are not identical to, those of Bcl-2, J. Cell Biol. 128: 1173 (1995).

    Google Scholar 

  60. M. Gonzalez-Garcia, R. Pérez-Ballestero, L. Ding, L. Duan, L.H. Boise, C.B. Thompson and G. Núiiez, bcl-XL is the major bc1-X mRNA form expressed during murine development and its product localizes to mitochondria, Development 120: 3033 (1994).

    Google Scholar 

  61. D.J. Kane, T.A. Sarafin, S. Auton, H. Hahn, F.B. Gralla, J.C. Valentine, T. Ord and D.E. Bredesen, Bcl-2 inhibition of neural cell death: decreased generation of reactive oxygen species, Science 262: 1274 (1993).

    Article  PubMed  CAS  Google Scholar 

  62. D. Hockenbery, Z. Oltvai, X.-M. Yin, C. Milliman and S.J. Korsmeyer, Bcl-2 functions in an antioxidant pathway to prevent apoptosis, Cell 75: 241 (1993).

    Article  PubMed  CAS  Google Scholar 

  63. M.D. Jacobson and M.C. Raff, Programmed cell death and Bcl-2 protection in very low oxygen, Nature 374: 814 (1995).

    Article  PubMed  CAS  Google Scholar 

  64. S. Shimizu, Y. Eguchi, H. Kosaka, W. Kamiike, H. Matsuda and Y. Tsujimoto, Prevention of hypoxia-induced cell death by Bel-2 and Bcl-XL, Nature 374: 811 (1995).r

    Google Scholar 

  65. G. Baffy, T. Miyashita, J.R. Williamson and J.C. Reed, Apoptosis induced by withdrawal of Interleukin-3 [IL-3] from an IL-3-dependent hematopoietic cell line associated with repartitioning of intracellular calcium and is blocked by enforced Bcl-2 oncoprotein production, J. Biol. Chem. 268: 6511 (1993).

    PubMed  CAS  Google Scholar 

  66. M. Lam, G. Dubyak, L. Chen, G. Nunez, R.L. Miesfeld and C.W. Distelhorst, Evidence that Bcl-2 represses apoptosis by regulating endoplasmic reticulum-associated Cat+ fluxes, Proc. Natl. Acad. Sci. USA 91: 6569 (1994).

    Article  PubMed  CAS  Google Scholar 

  67. J.J. Ryan, E. Prochownik, C.A. Gottlieb, I.J. Apel, R. Merino, G. Nunez and M.F. Clarke, c-myc and Bcl-2 modulates p53 function by altering p53 subcellular trafficking during the cell cycle, Proc. Natl. Acad. Sci. USA 91: 5878 (1994).

    Article  PubMed  CAS  Google Scholar 

  68. W. Meikrantz, S. Gisselbrecht, S.W. Tam and R. Schlegel, Activation of cyclin A-dependent protein kinases during apoptosis, Proc. Natl. Acad. Sci. USA 91: 3754 (1994).

    Article  PubMed  CAS  Google Scholar 

  69. J. Yuan, S. Shaham, S. Ledoux, H.M. Ellis and H.R. Horvitz, The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme, Cell 75: 641 (1993).

    Article  PubMed  CAS  Google Scholar 

  70. A.M. Chinnaiyan, K. Orth, K. O’Rourke, H. Duan, G.G. Poirier and V.M. Dixit, Molecular odering of the cell death pathway: Bcl-2 and Bcl-XL function upstream of the CED-3-like apoptotic proteases, J. Biol. Chem. in press.: (1996).

    Google Scholar 

  71. C.A. Boulakia, G. Chen, F.W.H. Ng, J.G. Teodoro, P.E. Branton, D.W. Nicholson, G.G. Poirier and G.C. Shore, Bcl-2 and adenovirus EIB 19 kDA protein prevent E1A-induced processing of CPP32 and cleavage of poly(ADP-ribose) polymerase, Oncogene 12: 29 (1996).

    Google Scholar 

  72. H.-G. Wang, T. Miyashita, S. Takayama, T. Sato, T. Torigoe, S. Krajewski, S. Tanaka, III Hovey,L., J. Troppmair, U.R. Rapp and J.C. Reed, Apoptosis regulation by interaction of Bcl-2 protein and Raf-1 kinase, Oncogene 9: 2751 (1994).

    PubMed  CAS  Google Scholar 

  73. M.J. Fernandez-Sarbia and J.R. Bischoff, Bel-2 associates with the ras-related protein R-ras p23, Nature 366: 274 (1993).

    Article  Google Scholar 

  74. H.-G. Wang, J.A. Millan, A.D. Cox, C.J. Der, U.R. Rapp, T. Beck, H. Zha and J.C. Reed, R-ras promotes apoptosis caused by growth factor deprivation via a Bel-2 suppressible mechanism, J. Cell Biol. 129: 1103 (1995).

    Article  PubMed  CAS  Google Scholar 

  75. H. Zha, C. Aime-Sempe, T. Sato and J.C. Reed, Pro-apoptotic protein Bax heterodimerizes with Bcl-2 and homodimerizes with Bax via a novel domain (BH3) distinct from BH 1 and BH2, J. Biol. Chem. in press (1996).

    Google Scholar 

  76. T. Sato, S. Irie, S. Krajewski and J.C. Reed, Cloning and sequencing of cDNA encoding rat bcl-2 protein, Gene 140: 291 (1994).

    Article  PubMed  CAS  Google Scholar 

  77. M. Hanada, C. Aimé-Sempé, T. Sato and J.C. Reed, Structure-function analysis of Bcl-2 protein: identification of conserved domains important for homodimerization with bc!-2 and heterodimerization with bax, J. Biol. Chem. 270: 11962 (1995).

    Article  PubMed  CAS  Google Scholar 

  78. T. Chittenden, C. Flemington, A.B. Houghton, R.G. Ebb, G.J. Gallo, B. Elangovan, G. Chinnadurai and R.J. Lutz, A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions, EMBOJ. 14: 5589 (1995).

    CAS  Google Scholar 

  79. J.J. Hunter and T.G. Parslow, A peptide sequence from Bax that converts Bcl-2 into an activator of apoptosis, J. Biol. Chem. in press (1996).

    Google Scholar 

  80. C. Borner, I. Martinou, C. Mattmann, M. Irmler, E. Scharer, J.-C. Martinou and J. Tschopp, The protein bcl-2alpha does not require membrane attachment, but two conserved domains to suppress apoptosis, J. Cell Biol. 126: 1059 (1994).

    Article  PubMed  CAS  Google Scholar 

  81. J.J. Hunter, B.L. Bond and T.G. Parslow, Functional dissection of the human Bcl-2 protein: sequence requirements for inhibition of apoptosis, Mol. Cell. Biol. in press (1996).

    Google Scholar 

  82. T. Subramanian, J.M. Boyd and G. Chinnadurai, Functional substitution identifies a cell survival promoting domain common to adenovirus ElB 19 kDa and Bcl-2 proteins, Oncogene 11: 2403 (1995).

    Google Scholar 

  83. X.M. Yin, Z.N. Oltvai and S.J. Korsmeyer, BH 1 and BH2 domains of bcl-2 are required for inhibition of apoptosis and heterodimerization with bax, Nature 369: 321 (1994).

    Article  PubMed  CAS  Google Scholar 

  84. S. Takayama, T. Sato, S. Krajewski, K. Kochel, S. Irie, J.A. Milian and J.C. Reed, Cloning and functional analysis of BAG-1: a novel Bcl-2 binding protein with anti-cell death activity, Cell 80: 279 (1995).

    Article  PubMed  CAS  Google Scholar 

  85. E.H.-Y. Cheng, B. Levine, L.H. Boise, C.B. Thompson and J.M. Hardwick, Bax-independent inhibition of apoptosis by Bc1-XL, Nature 379: 554 (1996).

    Article  PubMed  CAS  Google Scholar 

  86. S.V. Razin and I.I. Gromova, The channels model of nuclear matrix structure, BioEssays 17: 443 (1995).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The La Jolla Cancer Research Foundation, 10901 N. Torrey Pines Road, La Jolla, California, 92037, USA

    John C. Reed, Hongbin Zha, Christine Aime-Sempe, Shinichi Takayama & Hong-Gang Wang

Authors
  1. John C. Reed
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hongbin Zha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christine Aime-Sempe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shinichi Takayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hong-Gang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of California, Irvine, Irvine, California, USA

    Sudhir Gupta

  2. University of Colorado Health Sciences Center, Denver, Colorado, USA

    J. John Cohen

Rights and permissions

Reprints and permissions

Copyright information

© 1996 Springer Science+Business Media New York

About this chapter

Cite this chapter

Reed, J.C., Zha, H., Aime-Sempe, C., Takayama, S., Wang, HG. (1996). Structure—Function Analysis of Bcl-2 Family Proteins. In: Gupta, S., Cohen, J.J. (eds) Mechanisms of Lymphocyte Activation and Immune Regulation VI. Advances in Experimental Medicine and Biology, vol 406. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-0274-0_10

Download citation

  • DOI: https://doi.org/10.1007/978-1-4899-0274-0_10

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4899-0276-4

  • Online ISBN: 978-1-4899-0274-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation