Deletion of the Cancer-amplified Coactivator AIB3 Results in Defective Placentation and Embryonic Lethality

The amplified in breast cancer-3 (AIB3, ASC-2, RAP250, PRIP, TRBP, NRC, or NcoA6) gene is characterized as a cancer-amplified transcriptional coactivator for nuclear receptors, which include the peroxisome proliferator-activated receptor γ (PPARγ). To assess its biological function, we deleted the...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-11, Vol.277 (47), p.45356-45360
Main Authors: Kuang, Shao-Qing, Liao, Lan, Zhang, Hao, Pereira, Fred A, Yuan, Yuhui, DeMayo, Francesco J, Ko, Lan, Xu, Jianming
Format: Article
Language:English
Subjects:
Animals
Body Constitution
Cells, Cultured
Embryo Loss
Embryo, Mammalian - anatomy & histology
Embryo, Mammalian - physiology
Female
Fetal Growth Retardation
Fibroblasts - cytology
Fibroblasts - metabolism
Gene Deletion
Genes, Reporter
Humans
Intracellular Signaling Peptides and Proteins
Mice
Mice, Knockout
Molecular Sequence Data
Nuclear Receptor Coactivators
Placenta - anatomy & histology
Placenta - physiology
Placentation
Pregnancy
Receptors, Cytoplasmic and Nuclear - metabolism
Recombination, Genetic
Transcription Factors - genetics
Transcription Factors - metabolism
Transcription, Genetic
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Summary:The amplified in breast cancer-3 (AIB3, ASC-2, RAP250, PRIP, TRBP, NRC, or NcoA6) gene is characterized as a cancer-amplified transcriptional coactivator for nuclear receptors, which include the peroxisome proliferator-activated receptor γ (PPARγ). To assess its biological function, we deleted the AIB3 gene in mice by homologous recombination. AIB3 +/− mice are developmentally normal and fertile. AIB3 −/− embryos exhibit growth restriction and lethality during 9.75–11.5 days postconception. The embryonic lethality is probably attributed to defects in the development of the placental vascular network and cardiac hypoplasia. These defects include the failure of labyrinthine development, the dilation of maternal blood sinuses, the massive erythrophagocytosis by trophoblasts, the alteration of trophoblast populations, and the lower proliferation of myocardium, which are similar to those encountered in mice lacking PPARγ or the PPARγ-binding protein (PBP, TRAP220, or DRIP205). In addition, the transcriptional activities of PPARγ are significantly affected in mouse embryonic fibroblasts lacking AIB3. These results suggest that AIB3 is required for PPARγ function in placental development and for normal heart development. These results also indicate that the biological function of AIB3 is not redundant with other classes of nuclear receptor coactivators such as PBP and members of the steroid receptor coactivator family.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.C200509200