DR5 knockout mice are compromised in radiation-induced apoptosis.
DR5 (also called TRAIL receptor 2 and KILLER) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (also called TRAIL and Apo2 ligand). DR5 is a transcriptional target of p53, and its overexpression induces cell death in vitro. However, the in vivo biology of DR5 has remained largely unexplored. To better understand the role of DR5 in development and in adult tissues, we have created a knockout mouse lacking DR5. This mouse is viable and develops normally with the exception of having an enlarged thymus. We show that DR5 is not expressed in developing embryos but is present in the decidua and chorion early in development. DR5-null mouse embryo fibroblasts expressing E1A are resistant to treatment with TRAIL, suggesting that DR5 may be the primary proapoptotic receptor for TRAIL in the mouse. When exposed to ionizing radiation, DR5-null tissues exhibit reduced amounts of apoptosis compared to wild-type thymus, spleen, Peyer's patches, and the white matter of the brain. In the ileum, colon, and stomach, DR5 deficiency was associated with a subtle phenotype of radiation-induced cell death. These results indicate that DR5 has a limited role during embryogenesis and early stages of development but plays an organ-specific role in the response to DNA-damaging stimuli.
Finnberg
Niklas
N
University of Pennsylvania, 415 Curie Blvd., CRB 437, Philadelphia, PA 19104, USA.
Gruber
Joshua J
JJ
Fei
Peiwen
P
Rudolph
Dorothea
D
Bric
Anka
A
Kim
Seok-Hyun
SH
Burns
Timothy F
TF
Ajuha
Hope
H
Page
Robert
R
Wu
Gen Sheng
GS
Chen
Youhai
Y
McKenna
W Gillies
WG
Bernhard
Eric
E
Lowe
Scott
S
Mak
Tak
T
El-Deiry
Wafik S
WS
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D020169:Caspases / Q000032:analysis / Q000378:metabolism; D002823:Chorion / Q000378:metabolism; D004249:DNA Damage; D003656:Decidua / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D015870:Gene Expression; D018390:Gene Targeting; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D011839:Radiation, Ionizing; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000502:physiology*; D017384:Sequence Deletion / Q000235:genetics; D013154:Spleen / Q000737:chemistry / Q000166:cytology / Q000528:radiation effects; D053221:TNF-Related Apoptosis-Inducing Ligand; D013950:Thymus Gland / Q000737:chemistry / Q000166:cytology / Q000528:radiation effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505640:Tnfrsf10b protein, mouse; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases