Home LiteratureArticle Details
PMID: 22560721 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Human embryonic stem cells have constitutively active Bax at the Golgi and are primed to undergo rapid apoptosis.

Molecular cell ·Vol. 46 ·No. 5 ·2012-06-08 ·Pages 573-83

Dumitru R, Gama V, Fagan BM, Bower JJ, Swahari V, Pevny LH, Deshmukh M

Abstract

Human embryonic stem (hES) cells activate a rapid apoptotic response after DNA damage but the underlying mechanisms are unknown. A critical mediator of apoptosis is Bax, which is reported to become active and translocate to the mitochondria only after apoptotic stimuli. Here we show that undifferentiated hES cells constitutively maintain Bax in its active conformation. Surprisingly, active Bax was maintained at the Golgi rather than at the mitochondria, thus allowing hES cells to effectively minimize the risks associated with having preactivated Bax. After DNA damage, active Bax rapidly translocated to the mitochondria by a p53-dependent mechanism. Interestingly, upon differentiation, Bax was no longer active, and cells were not acutely sensitive to DNA damage. Thus, maintenance of Bax in its active form is a unique mechanism that can prime hES cells for rapid death, likely to prevent the propagation of mutations during the early critical stages of embryonic development.

MeSH Terms
Acetylation Antigens, Nuclear/metabolism Apoptosis Biological Transport DNA Damage DNA-Binding Proteins/metabolism Embryonic Stem Cells/cytology,metabolism Gene Silencing Genes, bcl-2 Golgi Apparatus/metabolism Humans Ku Autoantigen Mitochondria/metabolism Tumor Suppressor Protein p53/physiology bcl-2-Associated X Protein/analysis,metabolism
Chemicals
Antigens, Nuclear BAX protein, human DNA-Binding Proteins Tumor Suppressor Protein p53 bcl-2-Associated X Protein Xrcc6 protein, human Ku Autoantigen
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Dumitru Raluca
Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Gama Vivian
Fagan B Matthew
Bower Jacquelyn J
Swahari Vijay
Pevny Larysa H
Deshmukh Mohanish
References (44)
44 references, click to expand
  1. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis.
    J Cell Biol. 2002 Dec 23;159(6):931-8 PMID: 12499352
  2. Embryonic stem cell lines derived from human blastocysts.
    Science. 1998 Nov 6;282(5391):1145-7 PMID: 9804556
  3. Self-renewal of human embryonic stem cells is supported by a shortened G1 cell cycle phase.
    J Cell Physiol. 2006 Dec;209(3):883-93 PMID: 16972248
  4. The BCL-2 family reunion.
    Mol Cell. 2010 Feb 12;37(3):299-310 PMID: 20159550
  5. Ionizing radiation induces ataxia telangiectasia mutated-dependent checkpoint signaling and G(2) but not G(1) cell cycle arrest in pluripotent human embryonic stem cells.
    Stem Cells. 2009 Aug;27(8):1822-35 PMID: 19544417
  6. The BCL-2 protein family: opposing activities that mediate cell death.
    Nat Rev Mol Cell Biol. 2008 Jan;9(1):47-59 PMID: 18097445
  7. Control of mitochondrial apoptosis by the Bcl-2 family.
    J Cell Sci. 2009 Feb 15;122(Pt 4):437-41 PMID: 19193868
  8. Baxbeta: a constitutively active human Bax isoform that is under tight regulatory control by the proteasomal degradation mechanism.
    Mol Cell. 2009 Jan 16;33(1):15-29 PMID: 19150424
  9. Bax and Bak coalesce into novel mitochondria-associated clusters during apoptosis.
    J Cell Biol. 2001 Jun 11;153(6):1265-76 PMID: 11402069
  10. PUMA, a novel proapoptotic gene, is induced by p53.
    Mol Cell. 2001 Mar;7(3):683-94 PMID: 11463392
  11. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis.
    Science. 2004 Feb 13;303(5660):1010-4 PMID: 14963330
  12. Apoptosis: controlled demolition at the cellular level.
    Nat Rev Mol Cell Biol. 2008 Mar;9(3):231-41 PMID: 18073771
  13. BH3-only proteins and their roles in programmed cell death.
    Oncogene. 2008 Dec;27 Suppl 1:S128-36 PMID: 19641498
  14. Overexpression of BCL2 enhances survival of human embryonic stem cells during stress and obviates the requirement for serum factors.
    Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3282-7 PMID: 21300885
  15. An inhibitor of Bcl-2 family proteins induces regression of solid tumours.
    Nature. 2005 Jun 2;435(7042):677-81 PMID: 15902208
  16. Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis.
    Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3668-72 PMID: 9108035
  17. Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells.
    J Biol Chem. 2001 Apr 13;276(15):11615-23 PMID: 11136736
  18. PUMA induces the rapid apoptosis of colorectal cancer cells.
    Mol Cell. 2001 Mar;7(3):673-82 PMID: 11463391
  19. Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming.
    Cell. 2008 Feb 22;132(4):567-82 PMID: 18295576
  20. Bcl-xL enhances single-cell survival and expansion of human embryonic stem cells without affecting self-renewal.
    Stem Cell Res. 2012 Jan;8(1):26-37 PMID: 22099018
  21. Bcl-x(L) retrotranslocates Bax from the mitochondria into the cytosol.
    Cell. 2011 Apr 1;145(1):104-16 PMID: 21458670
  22. Bax-inhibiting peptides derived from Ku70 and cell-penetrating pentapeptides.
    Biochem Soc Trans. 2007 Aug;35(Pt 4):797-801 PMID: 17635151
  23. Brefeldin A causes disassembly of the Golgi complex and accumulation of secretory proteins in the endoplasmic reticulum.
    J Biol Chem. 1988 Dec 5;263(34):18545-52 PMID: 3192548
  24. Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation.
    Cell Death Differ. 2007 Dec;14(12):2058-67 PMID: 17885668
  25. BAX unleashed: the biochemical transformation of an inactive cytosolic monomer into a toxic mitochondrial pore.
    Trends Biochem Sci. 2011 Dec;36(12):642-52 PMID: 21978892
  26. p53 has a direct apoptogenic role at the mitochondria.
    Mol Cell. 2003 Mar;11(3):577-90 PMID: 12667443
  27. Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis.
    Mol Cell. 2004 Mar 12;13(5):627-38 PMID: 15023334
  28. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis.
    Science. 2000 May 12;288(5468):1053-8 PMID: 10807576
  29. Ku70 acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors.
    Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4842-7 PMID: 15778293
  30. Bax-inhibiting peptide derived from mouse and rat Ku70.
    Biochem Biophys Res Commun. 2004 Sep 3;321(4):961-6 PMID: 15358121
  31. Regulation of apoptosis and differentiation by p53 in human embryonic stem cells.
    J Biol Chem. 2007 Feb 23;282(8):5842-52 PMID: 17179143
  32. The Golgi and endoplasmic reticulum remain independent during mitosis in HeLa cells.
    Mol Biol Cell. 1998 Mar;9(3):623-35 PMID: 9487131
  33. Tracking BAX once its trigger is pulled.
    Cell Cycle. 2011 Mar 15;10(6):868-70 PMID: 21325897
  34. Etoposide induces MLL rearrangements and other chromosomal abnormalities in human embryonic stem cells.
    Carcinogenesis. 2009 Sep;30(9):1628-37 PMID: 19587093
  35. Nonionic detergents induce dimerization among members of the Bcl-2 family.
    J Biol Chem. 1997 May 23;272(21):13829-34 PMID: 9153240
  36. BH3-only proteins: Orchestrators of apoptosis.
    Biochim Biophys Acta. 2011 Apr;1813(4):508-20 PMID: 21146563
  37. Survival responses of human embryonic stem cells to DNA damage.
    J Cell Physiol. 2009 Sep;220(3):586-92 PMID: 19373864
  38. Movement of Bax from the cytosol to mitochondria during apoptosis.
    J Cell Biol. 1997 Dec 1;139(5):1281-92 PMID: 9382873
  39. p53 is required for etoposide-induced apoptosis of human embryonic stem cells.
    Stem Cell Res. 2007 Nov;1(2):116-28 PMID: 19383392
  40. Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis.
    J Cell Sci. 2009 Aug 15;122(Pt 16):2801-8 PMID: 19795525
  41. Preservation of genomic integrity in mouse embryonic stem cells.
    Adv Exp Med Biol. 2010;695:59-75 PMID: 21222199
  42. Mitochondria and cell death: outer membrane permeabilization and beyond.
    Nat Rev Mol Cell Biol. 2010 Sep;11(9):621-32 PMID: 20683470
  43. BCL-2 family members and the mitochondria in apoptosis.
    Genes Dev. 1999 Aug 1;13(15):1899-911 PMID: 10444588
  44. Multilineage differentiation from human embryonic stem cell lines.
    Stem Cells. 2001;19(3):193-204 PMID: 11359944
Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2012.04.002
Published
2012-06-08
Epub
2012-00-03
Pages
573-83
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC3372694
Subset
IM
Grants
NIGMS NIH HHS · GM078366 · United States
NIGMS NIH HHS · R01 GM078366 · United States
NIGMS NIH HHS · R01 GM078366-02 · United States
NIGMS NIH HHS · R01 GM078366-03S1 · United States
NIGMS NIH HHS · R01 GM078366-01 · United States
NIGMS NIH HHS · R01 GM078366-04 · United States
NINDS NIH HHS · 5 P30 NS04892 · United States
NIGMS NIH HHS · R01 GM078366-03 · United States
Corrections
CommentIn
PMID: 22681883
External Links
PubMed source DOI: 10.1016/j.molcel.2012.04.002 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