Bax and Bak do not exhibit functional redundancy in mediating radiation-induced endothelial apoptosis in the intestinal mucosa Journal Article
| Authors: | Rotolo, J. A.; Maj, J. G.; Feldman, R.; Ren, D.; Haimovitz-Friedman, A.; Cordon-Cardo, C.; Cheng, E. H. Y.; Kolesnick, R.; Fuks, Z. |
| Article Title: | Bax and Bak do not exhibit functional redundancy in mediating radiation-induced endothelial apoptosis in the intestinal mucosa |
| Abstract: | Purpose: To address in vivo the issue of whether Bax and Bak are functionally redundant in signaling apoptosis, capable of substituting for each other. Methods and Materials: Mice were exposed to whole-body radiation, and endothelial cell apoptosis was quantified using double immunostaining with TUNEL and anti-CD31 antibody. Crypt survival was determined at 3.5 days after whole-body radiation by the microcolony survival assay. Actuarial animal survival was calculated by the product-limit Kaplan-Meier method, and autopsies were performed to establish cause of death. Results: Radiation exposure of Bax- and Bak-deficient mice, both expressing a wild-type acid sphingomyelinase (ASMase) phenotype, indicated that Bax and Bak are both mandatory, though mutually independent, for the intestinal endothelial apoptotic response. However, neither affected epithelial apoptosis at crypt positions 4-5, indicating specificity toward endothelium. Furthermore, Bax deficiency and Bak deficiency each individually mimicked ASMase deficiency in inhibiting crypt lethality in the microcolony assay and in rescuing mice from the lethal gastrointestinal syndrome. Conclusions: The data indicate that Bax and Bak have nonredundant functional roles in the apoptotic response of the irradiated intestinal endothelium. The observation that Bax deficiency and Bak deficiency also protect crypts in the microcolony assay provides strong evidence that the microvascular apoptotic component is germane to the mechanism of radiation-induced damage to mouse intestines, regulating reproductive cell death of crypt stem cell clonogens. © 2008 Elsevier Inc. All rights reserved. |
| Keywords: | immunohistochemistry; signal transduction; controlled study; unclassified drug; nonhuman; protein function; biological markers; animal cell; mouse; phenotype; animals; mice; animal tissue; cell death; cell survival; apoptosis; radiation; animal experiment; animal model; radiation injury; wild type; mice, inbred c57bl; radiation exposure; endothelium cell; endothelial cells; cause of death; whole body radiation; cell culture; endothelium, vascular; quantitative analysis; bioassay; radiation injuries; protein deficiency; kaplan meier method; autopsy; gastrointestinal tract; nick end labeling; intestine, small; colony-forming units assay; gastrointestinal disease; biological organs; jejunum; whole-body irradiation; calculation; lymphocyte antibody; crypt; intestine mucosa; sphingomyelin phosphodiesterase; dosimeters; mice, inbred c3h; acid sphingomyelinase; protein bax; antigens, cd31; in situ nick-end labeling; intestinal mucosa; protein bak; bcl-2 homologous antagonist-killer protein; bcl-2-associated x protein; endothelial cell apoptosis; gastrointestinal tracts; cd31 antibody |
| Journal Title: | International Journal of Radiation Oncology, Biology, Physics |
| Volume: | 70 |
| Issue: | 3 |
| ISSN: | 0360-3016 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2008-03-01 |
| Start Page: | 804 |
| End Page: | 815 |
| Language: | English |
| DOI: | 10.1016/j.ijrobp.2007.11.043 |
| PUBMED: | 18191336 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 16" - "Export Date: 17 November 2011" - "CODEN: IOBPD" - "Source: Scopus" |
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