BCL-XL exerts a protective role against anemia caused by radiation-induced kidney damage.
Anemia
/ prevention & control
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Apoptosis Regulatory Proteins
/ genetics
Bcl-2-Like Protein 11
/ genetics
DNA Damage
Female
Gamma Rays
Hematologic Neoplasms
/ pathology
Inflammation
Kidney
/ metabolism
Liver
/ pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Proto-Oncogene Proteins c-bcl-2
/ genetics
Transcriptome
Tumor Suppressor Proteins
/ genetics
bcl-X Protein
/ deficiency
BCL-XL
BH3-mimetic drugs
DNA damage
apoptosis
kidney failure
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
15 12 2020
15 12 2020
Historique:
received:
07
05
2020
revised:
06
10
2020
accepted:
15
10
2020
pubmed:
26
11
2020
medline:
13
4
2021
entrez:
25
11
2020
Statut:
ppublish
Résumé
Studies of gene-targeted mice identified the roles of the different pro-survival BCL-2 proteins during embryogenesis. However, little is known about the role(s) of these proteins in adults in response to cytotoxic stresses, such as treatment with anti-cancer agents. We investigated the role of BCL-XL in adult mice using a strategy where prior bone marrow transplantation allowed for loss of BCL-XL exclusively in non-hematopoietic tissues to prevent anemia caused by BCL-XL deficiency in erythroid cells. Unexpectedly, the combination of total body γ-irradiation (TBI) and genetic loss of Bcl-x caused secondary anemia resulting from chronic renal failure due to apoptosis of renal tubular epithelium with secondary obstructive nephropathy. These findings identify a critical protective role of BCL-XL in the adult kidney and inform on the use of BCL-XL inhibitors in combination with DNA damage-inducing drugs for cancer therapy. Encouragingly, the combination of DNA damage-inducing anti-cancer therapy plus a BCL-XL inhibitor could be tolerated in mice, at least when applied sequentially.
Identifiants
pubmed: 33236795
doi: 10.15252/embj.2020105561
pmc: PMC7737616
doi:
Substances chimiques
Antineoplastic Agents
0
Apoptosis Regulatory Proteins
0
Bcl-2-Like Protein 11
0
Bcl2l1 protein, mouse
0
Bcl2l11 protein, mouse
0
PUMA protein, mouse
0
Proto-Oncogene Proteins c-bcl-2
0
Tumor Suppressor Proteins
0
bcl-X Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e105561Subventions
Organisme : Department of Health, Australian Government | National Health and Medical Research Council (NHMRC)
ID : 1016701
Organisme : Department of Health, Australian Government | National Health and Medical Research Council (NHMRC)
ID : 1016647
Organisme : Department of Health, Australian Government | National Health and Medical Research Council (NHMRC)
ID : 1020363
Organisme : Department of Health, Australian Government | National Health and Medical Research Council (NHMRC)
ID : 1145728
Organisme : Deutsche Krebshilfe (German Cancer Aid)
Informations de copyright
© 2020 The Authors.
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