TY - JOUR
T1 - Deletions of retinoblastoma 1 (Rb1) and its repressing target S phase kinase-associated protein 2 (Skp2) are synthetic lethal in mouse embryogenesis
AU - Zhao, Hongling
AU - Wang, Hongbo
AU - Bauzon, Frederick
AU - Lu, Zhonglei
AU - Fu, Hao
AU - Cui, Jinhua
AU - Zhu, Liang
N1 - Funding Information:
This work was supported by National Institutes of Health Grants RO1CA127901and RO1CA131421 (to L. Z.), Albert Einstein Comprehensive Cancer Research Center Grant 5P30CA13330, and Liver Research Center Grant 5P30DK061153.
PY - 2016/5/6
Y1 - 2016/5/6
N2 - Tumor suppressor pRb represses Skp2, a substrate-recruiting subunit of the SCFSkp2 ubiquitin ligase. Rb1+/- mice incur "twohit" pituitary tumorigenesis; Skp2-/-;Rb1+/- mice do not. Rb1-/- embryos die on embryonic day (E) 14.5-15.5. Here, we report that Skp2-/-;Rb1-/- embryos died on E11.5, establishing an organismal level synthetic lethal relationship between Rb1 and Skp2. On E10.5, Rb1-/- placentas showed similarly active proliferation and similarly inactive apoptosis as WT placenta, whereas Rb1-/- embryos showed ectopic proliferation without increased apoptosis in the brain. Combining Skp2-/- did not reduce proliferation or increase apoptosis in the placentas but induced extensive apoptosis in the brain. We conditionally deleted Rb1 in neuronal lineage with Nes-Cre and reproduced the brain apoptosis in E13.5 Nes-Cre;Rb1lox/lox;Skp2-/- embryos, demonstrating their synthetic lethal relationship at a cell autonomous level. Nes-Cre-mediated Rb1 deletion increased expression of proliferative E2F target genes in the brains of Skp2+/+ embryos; the increases rose higher with activation of expression of apoptotic E2F target genes in Skp2-/- embryos. The brain apoptosis was independent of p53 but coincident with proliferation. The highly activated expression of proliferative and apoptotic E2F target genes subsided with gradually reduced roles of Skp2 in preventing p27 protein accumulation in the brain in late gestation, allowing the embryos to reach full term with normally sized brains. These findings establish that Rb1 and Skp2 deletions are synthetic lethal and suggest how this lethal relationship might be circumvented, which could help design better therapies for pRb-deficient cancer.
AB - Tumor suppressor pRb represses Skp2, a substrate-recruiting subunit of the SCFSkp2 ubiquitin ligase. Rb1+/- mice incur "twohit" pituitary tumorigenesis; Skp2-/-;Rb1+/- mice do not. Rb1-/- embryos die on embryonic day (E) 14.5-15.5. Here, we report that Skp2-/-;Rb1-/- embryos died on E11.5, establishing an organismal level synthetic lethal relationship between Rb1 and Skp2. On E10.5, Rb1-/- placentas showed similarly active proliferation and similarly inactive apoptosis as WT placenta, whereas Rb1-/- embryos showed ectopic proliferation without increased apoptosis in the brain. Combining Skp2-/- did not reduce proliferation or increase apoptosis in the placentas but induced extensive apoptosis in the brain. We conditionally deleted Rb1 in neuronal lineage with Nes-Cre and reproduced the brain apoptosis in E13.5 Nes-Cre;Rb1lox/lox;Skp2-/- embryos, demonstrating their synthetic lethal relationship at a cell autonomous level. Nes-Cre-mediated Rb1 deletion increased expression of proliferative E2F target genes in the brains of Skp2+/+ embryos; the increases rose higher with activation of expression of apoptotic E2F target genes in Skp2-/- embryos. The brain apoptosis was independent of p53 but coincident with proliferation. The highly activated expression of proliferative and apoptotic E2F target genes subsided with gradually reduced roles of Skp2 in preventing p27 protein accumulation in the brain in late gestation, allowing the embryos to reach full term with normally sized brains. These findings establish that Rb1 and Skp2 deletions are synthetic lethal and suggest how this lethal relationship might be circumvented, which could help design better therapies for pRb-deficient cancer.
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U2 - 10.1074/jbc.M116.718049
DO - 10.1074/jbc.M116.718049
M3 - Article
C2 - 26966181
AN - SCOPUS:84966440010
SN - 0021-9258
VL - 291
SP - 10201
EP - 10209
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 19
ER -