Selective Suppression of a Subset of Bax-dependent Neuronal Death by a Cell Permeable Peptide Inhibitor of Bax, BIP

다국어 초록 (Multilingual Abstract)

Bax, a pro-apoptotic member of Bcl-2 family
proteins, plays a central role in the mitochondria-dependent
apoptosis. Apoptotic signals induce the translocation of Bax
from cytosol into the mitochondria, which triggers the
release of apoptogenic molecules such as cytochrome C
and apoptosis-inducing factor, AIF. Bax-inhibiting peptide
(BIP) is a cell permeable peptide comprised of five amino
acids designed from the Bax-interaction domain of Ku70.
Because BIP inhibits Bax translocation and Bax-mediated
release of cytochrome C, BIP suppresses Bax-dependent
apoptosis. In this study, we observed that BIP inhibited
staurosporine-induced neuronal death in cultured cerebral
cortex and cerebellar granule cells, but BIP failed to rescue
granule cells from trophic signal deprivation-induced neuronal
death, although both staurosporine-induced and trophic
signal deprivation-induced neuronal death are dependent
on Bax. These findings suggest that the mechanisms of the
Bax activation may differ depending on the type of cell death
induction, and thus BIP exhibits selective suppression of a
subtype of Bax-dependent neuronal death.

다국어 초록 (Multilingual Abstract)

Bax, a pro-apoptotic member of Bcl-2 family
proteins, plays a central role in the mitochondria-dependent
apoptosis. Apoptotic signals induce the translocation of Bax
from cytosol into the mitochondria, which triggers the
release of apoptogenic molecules such as cytochrome C
and apoptosis-inducing factor, AIF. Bax-inhibiting peptide
(BIP) is a cell permeable peptide comprised of five amino
acids designed from the Bax-interaction domain of Ku70.
Because BIP inhibits Bax translocation and Bax-mediated
release of cytochrome C, BIP suppresses Bax-dependent
apoptosis. In this study, we observed that BIP inhibited
staurosporine-induced neuronal death in cultured cerebral
cortex and cerebellar granule cells, but BIP failed to rescue
granule cells from trophic signal deprivation-induced neuronal
death, although both staurosporine-induced and trophic
signal deprivation-induced neuronal death are dependent
on Bax. These findings suggest that the mechanisms of the
Bax activation may differ depending on the type of cell death
induction, and thus BIP exhibits selective suppression of a
subtype of Bax-dependent neuronal death.

참고문헌 (Reference)

1 Gallo V, "The role of depolarization in the survival and differentiation of cerebellar granule cells in culture" 7 : 2203-2213, 1987

2 Qin Q, "The role of Bax-inhibiting peptide in retinal ganglion cell apoptosis after optic nerve transection" 372 : 17-21, 2004

3 Villunger A, "Strasser A (2003) p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa" 302 : 1036-1038, 2003

4 Yao CJ, "Roles of thapsigarginsensitive Ca2+ stores in the survival of developing cultured neurons" 73 : 457-465, 1999

5 Karbowski M, "Role of Bax and Bak in mitochondrial morphogenesis" 658-662, 2006

6 Sun,W, "Response of motoneurons to neonatal sciatic nerve axotomy in Bax-knockout mice" 24 : 875-886, 2003

7 Oakes SA, "Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum" 105-110, 2005

8 Sun W, "Oppenheim RW (2003) Neuromuscular development after the prevention of naturally occurring neuronal death by Bax deletion" 23 : 7298-7310, 2003

9 Wolter KG, "Movement of Bax from the cytosol to mitochondria during apoptosis" 139 : 1281-1292, 1997

10 Mignotte B, "Mitochondria and apoptosis" 252 : 1-15, 1998

11 Garrido C, "Mechanisms of cytochrome c release from mitochondria" 13 : 1432-1433, 2006

12 Sun W, "Localization and functional role of hepatocyte growth factor (HGF) and its receptor c-met in the rat developing cerebral cortex" 103 : 36-48, 2002

13 Sawada M, "Ku70 suppresses the apoptotic translocation of Bax to mitochondria" 5 : 320-329, 2003

14 Jang JW, "Isoform-specific ras activation and oncogene dependence during MYC-and Wntinduced mammary tumorigenesis.Mol Cell Biol" 26 : 8109-8121, 2006

15 D’Mello SR, "Induction of apoptosis in cerebellar granule neurons by low potassium: inhibition of death by insulin-like growth factor I and cAMP" 10989-10993, 1993

16 Putcha GV, "Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis" 29 : 615-628, 2001

17 Zhong J, "High K+ and IGF-1 protect cerebellar granule neurons via distinct signaling pathways" 75 : 794-806, 2004

18 Yu LY, "GDNF-deprived sympathetic neurons die via a novel nonmitochondrial pathway" 163 : 987-997, 2003

19 Zhuang J, "Emerging role of Mcl-1 in actively counteracting BH3-only proteins in apoptosis" 13 : 1263-1267, 2006

20 Leber B, "Embedded together: the life and death consequences of interaction of the Bcl-2 family with membranes" 12 : 897-911, 2007

21 Whitfield J, "Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release" 29 : 629-643, 2001

22 Sawada M, "Cytoprotective membrane-permeable peptides designed from the Baxbinding domain of Ku70" 352-357, 2003

23 Gould TW, "Complete dissociation of motor neuron death from motor dysfunction by Bax deletion in a mouse model of ALS" 26 : 8774-8786, 2006

24 Moran J, "Caspase-3 expression by cerebellar granule neurons is regulated by calcium and cyclic AMP" \ 73 : 568-577, 1999

25 Nardi N, "Biochemical and temporal analysis of events associated with apoptosis induced by lowering the extracellular potassium concentration in mouse cerebellar granule neurons" 68 : 750-759, 1997

26 Kuwana T, "Bcl-2-family proteins and the role of mitochondria in apoptosis" 15 : 691-699, 2003

27 Levine B, "Bcl-2 family members: dual regulators of apoptosis and autophagy" 4 : 600-606, 2008

28 Yoshi T, "Baxinhibiting peptide derived from mouse and rat Ku70" 321 : 961-966, 2004

29 Gomez JA, "Bax-inhibiting peptides derived from Ku70 and cell-penetrating pentapeptides" 35 : 797-801, 2007

30 Li Y, "Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation" 14 : 2058-2067, 2007

31 Knudson CM, "Bax-deficient mice with lymphoid hyperplasia and male germ cell death" 270 : 96-99, 1995

32 Shi J, "Bax limits adult neural stem cell persistence through caspase and IP3 receptor activation" 12 : 1601-1612, 2005

33 Chiesa R,Piccardo P,Dossena S,Nowoslawski L,Roth KA.Ghetti B,and Harris DA, "Bax deletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease" 238-243, 2005

34 Vila M, "Bax ablation prevents dopaminergic neurodegeneration in the 1- methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease" 2837-2842, 2001

35 Fletcher JI, "BH3-only proteins: orchestrating cell death" 13 : 1268-1271, 2006

36 Toescu EC, "Activity of voltage-operated calcium channels in rat cerebellar granule neurons and neuronal survival" 94 : 561-570, 1999