Home LiteratureArticle Details
PMID: 11163212 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues.

Molecular cell ·Vol. 6 ·No. 6 ·2000-12-00 ·Pages 1389-99

Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA, Ulrich E, Waymire KG, Mahar P, Frauwirth K, Chen Y, Wei M, Eng VM, Adelman DM, Simon MC, Ma A, Golden JA, Evan G, Korsmeyer SJ, MacGregor GR, Thompson CB

Abstract

Proapoptotic Bcl-2 family members have been proposed to play a central role in regulating apoptosis. However, mice lacking bax display limited phenotypic abnormalities. As presented here, bak(-/-) mice were found to be developmentally normal and reproductively fit and failed to develop any age-related disorders. However, when Bak-deficient mice were mated to Bax-deficient mice to create mice lacking both genes, the majority of bax(-/-)bak(-/-) animals died perinatally with fewer than 10% surviving into adulthood. bax(-/-)bak(-/-) mice displayed multiple developmental defects, including persistence of interdigital webs, an imperforate vaginal canal, and accumulation of excess cells within both the central nervous and hematopoietic systems. Thus, Bax and Bak have overlapping roles in the regulation of apoptosis during mammalian development and tissue homeostasis.

MeSH Terms
Abnormalities, Multiple/genetics Animals Apoptosis/drug effects,radiation effects Brain/abnormalities Cells, Cultured Crosses, Genetic Embryonic and Fetal Development/genetics Etoposide/pharmacology Female Gene Deletion Gene Targeting Genes, Essential/genetics Hematopoietic Stem Cells/metabolism,pathology Histocytochemistry Kidney/abnormalities,pathology Lymphoid Tissue/abnormalities,pathology Male Membrane Proteins/genetics,metabolism Mice Mice, Knockout Phenotype Proto-Oncogene Proteins/genetics,metabolism Proto-Oncogene Proteins c-bcl-2/genetics,metabolism Spleen/abnormalities,pathology Thymus Gland/abnormalities,pathology bcl-2 Homologous Antagonist-Killer Protein bcl-2-Associated X Protein fas Receptor/physiology
Chemicals
Bak1 protein, mouse Bax protein, mouse Membrane Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 bcl-2 Homologous Antagonist-Killer Protein bcl-2-Associated X Protein fas Receptor Etoposide
Authors & Affiliations
21 authors, click to expand affiliations / ORCID
Lindsten T
Department of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ross A J
King A
Zong W X
Rathmell J C
Shiels H A
Ulrich E
Waymire K G
Mahar P
Frauwirth K
Chen Y
Wei M
Eng V M
Adelman D M
Simon M C
Ma A
Golden J A
Evan G
Korsmeyer S J
MacGregor G R
Thompson C B
References (46)
46 references, click to expand
  1. Localization of bcl-2, bax, and bcl-x mRNAs in the developing inner ear of the mouse.
    Brain Res. 1996 Jul 8;726(1-2):123-8 PMID: 8836552
  2. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis.
    Science. 1997 Feb 21;275(5303):1132-6 PMID: 9027315
  3. Apoptosis by death factor.
    Cell. 1997 Feb 7;88(3):355-65 PMID: 9039262
  4. Bik and Bak induce apoptosis downstream of CrmA but upstream of inhibitor of apoptosis.
    J Biol Chem. 1997 Apr 4;272(14):8841-4 PMID: 9082997
  5. Mouse vaginal opening is an apoptosis-dependent process which can be prevented by the overexpression of Bcl2.
    Dev Biol. 1997 Apr 1;184(1):115-21 PMID: 9142988
  6. Modulation of cell death in yeast by the Bcl-2 family of proteins.
    J Biol Chem. 1997 Jun 13;272(24):15547-52 PMID: 9182591
  7. Gene structure, cDNA sequence, and expression of murine Bak, a proapoptotic Bcl-2 family member.
    Genomics. 1997 Sep 1;44(2):195-200 PMID: 9299236
  8. Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria.
    Cell. 1997 Nov 28;91(5):627-37 PMID: 9393856
  9. Bax directly induces release of cytochrome c from isolated mitochondria.
    Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):4997-5002 PMID: 9560217
  10. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9.
    Cell. 1998 Aug 7;94(3):325-37 PMID: 9708735
  11. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors.
    Cell. 1998 Aug 21;94(4):481-90 PMID: 9727491
  12. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis.
    Cell. 1998 Aug 21;94(4):491-501 PMID: 9727492
  13. The Bcl-2 protein family: arbiters of cell survival.
    Science. 1998 Aug 28;281(5381):1322-6 PMID: 9735050
  14. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development.
    Cell. 1998 Sep 18;94(6):727-37 PMID: 9753320
  15. Apaf1 is required for mitochondrial pathways of apoptosis and brain development.
    Cell. 1998 Sep 18;94(6):739-50 PMID: 9753321
  16. Cell death in development.
    Cell. 1999 Jan 22;96(2):245-54 PMID: 9988219
  17. Molecular characterization of mitochondrial apoptosis-inducing factor.
    Nature. 1999 Feb 4;397(6718):441-6 PMID: 9989411
  18. A new mouse insertional mutation that causes sensorineural deafness and vestibular defects.
    Genetics. 1999 Aug;152(4):1691-9 PMID: 10430593
  19. Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis.
    Nature. 1999 Aug 26;400(6747):886-91 PMID: 10476969
  20. Multilineage embryonic hematopoiesis requires hypoxic ARNT activity.
    Genes Dev. 1999 Oct 1;13(19):2478-83 PMID: 10521392
  21. The pro-apoptotic proteins, Bid and Bax, cause a limited permeabilization of the mitochondrial outer membrane that is enhanced by cytosol.
    J Cell Biol. 1999 Nov 15;147(4):809-22 PMID: 10562282
  22. Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane.
    Mol Cell Biol. 2000 Feb;20(3):929-35 PMID: 10629050
  23. Adult Apaf-1-deficient mice exhibit male infertility.
    Dev Biol. 2000 Feb 15;218(2):248-58 PMID: 10656767
  24. Generalized potential of adult neural stem cells.
    Science. 2000 Jun 2;288(5471):1660-3 PMID: 10834848
  25. Apoptotic pathways: paper wraps stone blunts scissors.
    Cell. 2000 Jul 7;102(1):1-4 PMID: 10929706
  26. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.
    Cell. 2000 Jul 7;102(1):33-42 PMID: 10929711
  27. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins.
    Cell. 2000 Jul 7;102(1):43-53 PMID: 10929712
  28. TRAF4 deficiency leads to tracheal malformation with resulting alterations in air flow to the lungs.
    Am J Pathol. 2000 Aug;157(2):679-88 PMID: 10934170
  29. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation.
    Nature. 1980 Apr 10;284(5756):555-6 PMID: 6245367
  30. p53 is required for radiation-induced apoptosis in mouse thymocytes.
    Nature. 1993 Apr 29;362(6423):847-9 PMID: 8479522
  31. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c.
    Genes Dev. 2000 Aug 15;14(16):2060-71 PMID: 10950869
  32. Thymocyte apoptosis induced by p53-dependent and independent pathways.
    Nature. 1993 Apr 29;362(6423):849-52 PMID: 8479523
  33. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death.
    Cell. 1993 Aug 27;74(4):609-19 PMID: 8358790
  34. Disappearance of the lymphoid system in Bcl-2 homozygous mutant chimeric mice.
    Science. 1993 Sep 17;261(5128):1584-8 PMID: 8372353
  35. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells.
    Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8424-8 PMID: 8378314
  36. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair.
    Cell. 1993 Oct 22;75(2):229-40 PMID: 8402909
  37. Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice.
    Science. 1995 Mar 10;267(5203):1506-10 PMID: 7878471
  38. Cloning of a bcl-2 homologue by interaction with adenovirus E1B 19K.
    Nature. 1995 Apr 20;374(6524):731-3 PMID: 7715729
  39. Induction of apoptosis by the Bcl-2 homologue Bak.
    Nature. 1995 Apr 20;374(6524):733-6 PMID: 7715730
  40. Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak.
    Nature. 1995 Apr 20;374(6524):736-9 PMID: 7715731
  41. Bax-deficient mice with lymphoid hyperplasia and male germ cell death.
    Science. 1995 Oct 6;270(5233):96-9 PMID: 7569956
  42. Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis.
    EMBO J. 1995 Dec 15;14(24):6136-47 PMID: 8557033
  43. Immunohistochemical analysis of in vivo patterns of Bak expression, a proapoptotic member of the Bcl-2 protein family.
    Cancer Res. 1996 Jun 15;56(12):2849-55 PMID: 8665525
  44. BAX is required for neuronal death after trophic factor deprivation and during development.
    Neuron. 1996 Sep;17(3):401-11 PMID: 8816704
  45. Progenitor cell proliferation outside the ventricular and subventricular zones during human brain development.
    J Neuropathol Exp Neurol. 1996 Dec;55(12):1253-8 PMID: 8957449
  46. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked.
    Science. 1997 Feb 21;275(5303):1129-32 PMID: 9027314
Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-2765
DOI
10.1016/s1097-2765(00)00136-2
Published
2000-12-00
Pages
1389-99
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC3057227
Subset
IM
Grants
NICHD NIH HHS · R01 HD036437-02 · United States
NICHD NIH HHS · R01 HD036437-03 · United States
NICHD NIH HHS · R01 HD036437-04 · United States
External Links
PubMed source DOI: 10.1016/s1097-2765(00)00136-2 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2