An anti-apoptotic peptide improves survival in lethal total body irradiation

McDunn, Jonathan E.; Muenzer, Jared T.; Dunne, Benjamin S.; Zhou, Anthony; Yuan, Kevin; Hoekzema, Andrew; Hilliard, Carolyn A.; Chang, Katherine; Davis, Christopher G.; McDonough, Jacquelyn S.; Hunt, Clayton R.; Grigsby, Perry W.; Piwnica‐Worms, David; Hotchkiss, Richard S.

doi:10.1016/j.bbrc.2009.03.080

Cited by 18 publications

(15 citation statements)

References 26 publications

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“…The most N-terminal BH region, the BH4 domain, distinguishes these antiapoptotic proteins from some, but not all, of their proapoptotic counterparts [4,5]. Interestingly, recent studies revealed that the BH4 helix, either as isolated peptide [6][7][8][9][10], or as an integral part of full-length Bcl-2 [11][12][13][14][15][16] possesses an antiapoptotic activity separated from or additive to the one mediated by the other three BH domains (BH1-3). At the mitochondria, the BH4 domain of Bcl-2 prevents BAX activation [9].…”

Section: Introductionmentioning

confidence: 99%

A double point mutation at residues Ile14 and Val15 of Bcl‐2 uncovers a role for the BH4 domain in both protein stability and function

et al. 2017

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B-cell lymphoma 2 (Bcl-2) protein is the archetype apoptosis suppressor protein. The N-terminal Bcl-2-homology 4 (BH4) domain of Bcl-2 is required for the antiapoptotic function of this protein at the mitochondria and endoplasmic reticulum (ER). The involvement of the BH4 domain in Bcl-2 0 s antiapoptotic functions has been proposed based on Gly-based substitutions of the Ile14/Val15 amino acids, two hydrophobic residues located in the center of Bcl-2 0 s BH4 domain. Following this strategy, we recently showed that a BH4-domain-derived peptide in which Ile14 and Val15 have been replaced by Gly residues, was unable to dampen proapoptotic Ca 2+ -release events from the ER. Here, we investigated the impact of these mutations on the overall structure, stability, and function of full-length Bcl-2 as a regulator of Ca 2+ signaling and cell death. Our results indicate that full-length Bcl-2 Ile14Gly/Val15Gly, in contrast to wild-type Bcl-2, (a) displayed severely reduced structural stability and a shortened protein halflife; (b) failed to interact with Bcl-2-associated X protein (BAX), to inhibit the inositol 1,4,5-trisphosphate receptor (IP 3 R) and to protect against Ca 2+ -mediated apoptosis. We conclude that the hydrophobic face of Bcl-2 0 s BH4 domain (Ile14, Val15) is an important structural regulatory element by affecting protein stability and turnover, thereby likely reducing Bcl-2 0 s ability to modulate the function of its targets, like IP 3 R and BAX. Therefore, Bcl-2 structure/function studies require pre-emptive and reliable determination of protein stability upon introduction of point mutations at the level of the BH4 domain. IntroductionApoptotic cell death is rigorously controlled by the intracellular ratio of anti-and pro-apoptotic B-cell lymphoma 2 (Bcl-2) proteins, a family of globular proteins acting upstream of mitochondrial outer membrane permeabilization (MOMP) and the cytosolic release of apoptogenic factors. Antiapoptotic Bcl-2 proteins, such as Bcl-2, B-cell lymphoma-extra large (Bcl-XL), and myeloid cell leukemia-1 (Mcl-1), guarantee cell survival mainly by neutralizing the pro-MOMP activity of their proapoptotic relatives [e.g., Bcl-2-associated X protein (BAX), Bcl-2 homologous antagonist killer (BAK)] at the mitochondria and by simultaneously restraining the flux of Ca 2+ ions between endoplasmic reticulum (ER) and mitochondria [1][2][3]. Bcl-2 and its prosurvival relatives contain all four of the structurally conserved and functionally essential a-helical regions defined as Bcl-2-homology domains (BH; Fig. 1A,B, upper panel). The most N-terminal BH region, the BH4 domain, distinguishes these antiapoptotic proteins from some, but not all, of their proapoptotic counterparts [4,5]. Interestingly, recent studies revealed that the BH4 helix, either as isolated peptide [6-10], or as an integral part of full-length Bcl-2 [11-16] possesses an antiapoptotic activity separated from or additive to the one mediated by the other three BH domains (BH1-3). At the mitochondria, the BH4 domain of Bcl-2 p...

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Section: Introductionmentioning

confidence: 99%

A double point mutation at residues Ile14 and Val15 of Bcl‐2 uncovers a role for the BH4 domain in both protein stability and function

et al. 2017

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“…Recent growing evidence suggests that such irradiation can influence immune system function (Gridley et al 2006;Hayashi et al 2005;McDunn et al 2009). It is subsequently important to investigate the effect of heavy ions on peripheral blood lymphocytes (PBL), a major component of the human immune system.…”

Section: Introductionmentioning

confidence: 99%

Early Effects of Low Dose ¹²C⁶⁺ Ion or X-Ray Irradiation on Peripheral Blood Lymphocytes of Patients with Alimentary Tract Cancer

Chen

et al. 2010

Dose-Response

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ᮀ The aim of this study was to examine the early effects of low dose 12 C 6+ irradiation or X-ray on peripheral blood lymphocytes (PBL) of patients with alimentary tract cancer and to explore mechanisms that may be involved in an antitumor immune response. We found that the percentage of T lymphocyte subsets, the mRNA expression levels of IL-2 and IFN-γ in PBL, and their protein levels in supernatant were significantly increased 24 hours after exposure to low dose radiation. The effects were more pronounced in the group receiving 0.05Gy 12 C 6+ ion irradiation than the group receiving X-ray irradiation. There was no significant change in the percentage of NK cell subsets and TNF-α production of PBL. Our study suggests that low dose irradiation could alleviate immune suppression caused by tumor burden and that the effect was more pronounced for 0.05Gy high linear energy transfer (LET) 12 C 6+ irradiation.

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“…Bcl-x L is a Bcl-x splicing variant and has anti-apoptotic ability [ 18 ]. Indeed, Bcl-x L overexpression reduces gamma irradiation–induced apoptosis, and BH4 peptides derived from Bcl-x L have been demonstrated to protect mice from death due to high-dose radiation [ 19 , 20 ]. Because BH4 forms part of the N-terminal of Bcl-x L , and because the antibody used in the present study recognizes 3–14 amino acids of Bcl-x L , these findings suggest that high and acute irradiation suppresses Bcl-x L expression, indicating the promotion of radiation damage, that is, apoptosis induction.…”

Section: Discussionmentioning

confidence: 99%

Differences in sustained alterations in protein expression between livers of mice exposed to high-dose-rate and low-dose-rate radiation

Nakajima

Wang

Ono

et al. 2017

Journal of Radiation Research

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Molecular mechanisms of radiation dose-rate effects are not well understood. Among many possibilities, long-lasting sustained alterations in protein levels would provide critical information. To evaluate sustained effects after acute and chronic radiation exposure, we analyzed alterations in protein expression in the livers of mice. Acute exposure consisted of a lethal dose of 8 Gy and a sublethal dose of 4 Gy, with analysis conducted 6 days and 3 months after irradiation, respectively. Chronic irradiation consisted of a total dose of 8 Gy delivered over 400 days (20 mGy/day). Analyses following chronic irradiation were done immediately and at 3 months after the end of the exposure. Based on antibody arrays of protein expression following both acute lethal and sublethal dose exposures, common alterations in the expression of two proteins were detected. In the sublethal dose exposure, the expression of additional proteins was altered 3 months after irradiation. Immunohistochemical analysis showed that the increase in one of the two commonly altered proteins, MyD88, was observed around blood vessels in the liver. The alterations in protein expression after chronic radiation exposure were different from those caused by acute radiation exposures. Alterations in the expression of proteins related to inflammation and apoptosis, such as caspase 12, were observed even at 3 months after the end of the chronic radiation exposure. The alterations in protein expression depended on the dose, the dose rate, and the passage of time after irradiation. These changes could be involved in long-term effects of radiation in the liver.

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An anti-apoptotic peptide improves survival in lethal total body irradiation

Cited by 18 publications

References 26 publications

A double point mutation at residues Ile14 and Val15 of Bcl‐2 uncovers a role for the BH4 domain in both protein stability and function

A double point mutation at residues Ile14 and Val15 of Bcl‐2 uncovers a role for the BH4 domain in both protein stability and function

Early Effects of Low Dose ¹²C⁶⁺ Ion or X-Ray Irradiation on Peripheral Blood Lymphocytes of Patients with Alimentary Tract Cancer

Differences in sustained alterations in protein expression between livers of mice exposed to high-dose-rate and low-dose-rate radiation

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An anti-apoptotic peptide improves survival in lethal total body irradiation

Cited by 18 publications

References 26 publications

A double point mutation at residues Ile14 and Val15 of Bcl‐2 uncovers a role for the BH4 domain in both protein stability and function

A double point mutation at residues Ile14 and Val15 of Bcl‐2 uncovers a role for the BH4 domain in both protein stability and function

Early Effects of Low Dose 12C6+ Ion or X-Ray Irradiation on Peripheral Blood Lymphocytes of Patients with Alimentary Tract Cancer

Differences in sustained alterations in protein expression between livers of mice exposed to high-dose-rate and low-dose-rate radiation

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Early Effects of Low Dose ¹²C⁶⁺ Ion or X-Ray Irradiation on Peripheral Blood Lymphocytes of Patients with Alimentary Tract Cancer