An anti-apoptotic peptide improves survival in lethal total body irradiation
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- 作者：Jonathan E. McDunn ; Jared T. Muenzer ; Benjamin Dunne ; Anthony Zhou ; Kevin Yuan ; Andrew Hoekzema ; Carolyn Hilliard ; Katherine C. Chang ; Christopher G. Davis ; Jacquelyn McDonough ; Clayton Hunt ; Perry Gr
- 关键词：Cell penetrating motif ; NLS ; TAT ; Bcl-2 ; BH4 ; Cell death ; Apoptosis ; Necrosis ; Total body irradiation
- 刊名：Biochemical and Biophysical Research Communications
- 出版年：2009
- 出版时间：15 May 2009
- 年：2009
- 卷：382
- 期：4
- 页码：657-662
- 全文大小：592 K
文摘
Cell penetrating peptides (CPPs) have been used to deliver the anti-apoptotic Bcl-xL-derived BH4 peptide to prevent injury-induced apoptosis both in vitro and in vivo. Here we demonstrate that the nuclear localization sequence (NLS) from the SV40 large T antigen has favorable properties for BH4 domain delivery to lymphocytes compared to sequences based on the HIV-1 TAT sequence. While both TAT-BH4 and NLS-BH4 protected primary human mononuclear cells from radiation-induced apoptotic cell death, TAT-BH4 caused persistent membrane damage and even cell death at the highest concentrations tested (5–10 μM) and correlated with in vivo toxicity as intravenous administration of TAT-BH4 caused rapid death. The NLS-BH4 peptide has significantly attenuated toxicity compared to TAT-BH4 and we established a dosing regimen of NLS-BH4 that conferred a significant survival advantage in a post-exposure treatment model of LD90 total body irradiation.