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Targeted Vpr-derived peptides reach mitochondria to induce apoptosis of alphaVbeta3-expressing endothelial cells.
- Source :
-
Cell death and differentiation [Cell Death Differ] 2007 Mar; Vol. 14 (3), pp. 422-35. Date of Electronic Publication: 2006 Aug 04. - Publication Year :
- 2007
-
Abstract
- The HIV-1 encoded apoptogenic protein Vpr induces mitochondrial membrane permeabilization (MMP) via interactions with the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT). We have designed a peptide, TEAM-VP, composed of two functional domains, one a tumor blood vessel RGD-like 'homing' motif and the other an MMP-inducing sequence derived from Vpr. When added to isolated mitochondria, TEAM-VP interacts with ANT and VDAC, reduces oxygen consumption and overcomes Bcl-2 protection to cause inner and outer MMP. TEAM-VP specifically recognizes cell-surface expressed alpha(V)beta(3) integrins, internalizes, temporarily localizes to lysosomes and progressively co-distributes with the mitochondrial compartment with no sign of lysosomal membrane permeabilization. Finally TEAM-VP reaches mitochondria of angiogenic endothelial cells to induce mitochondrial fission, dissipation of the mitochondrial transmembrane potential (DeltaPsi(m)), cytochrome c release and apoptosis hallmarks. Hence, this chimeric peptide constitutes the first example of a virus-derived mitochondriotoxic compound as a candidate to kill selectively tumor neo-endothelia.
- Subjects :
- Amino Acid Sequence
Animals
Apoptosis
Cell Survival
Dose-Response Relationship, Drug
Endothelial Cells metabolism
Gene Products, vpr pharmacology
Humans
Lysosomes metabolism
Mice
Mice, Inbred BALB C
Mitochondrial Membranes metabolism
Molecular Sequence Data
Peptides pharmacology
Permeability
Endothelial Cells physiology
Gene Products, vpr pharmacokinetics
Integrin alphaVbeta3 metabolism
Mitochondria metabolism
Peptides pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1350-9047
- Volume :
- 14
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cell death and differentiation
- Publication Type :
- Academic Journal
- Accession number :
- 16888644
- Full Text :
- https://doi.org/10.1038/sj.cdd.4402018