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The cooperative function of nuclear receptor coactivator 1 (NCOA1) and NCOA3 in placental development and embryo survival.

ABSTRACT: Nuclear receptor coactivator 1 [NCOA1/steroid receptor coactivator (SRC)-1] and NCOA3 (SRC-3/AIB1/ACTR) constitute two thirds of the SRC (steroid receptor coactivator) family. Although in vitro experiments have suggested overlapping functions between NCOA1 and NCOA3, their in vivo functional relationship is poorly understood. In this study, NCOA1 and NCOA3 double knockout mice were generated to determine the compensatory roles of NCOA1 and NCOA3 in development. NCOA1(-/-) mice survived normally, whereas most NCOA3(-/-) embryos were viable at embryonic d 13.5 (E13.5). In contrast, the majority of double-knockout (DKO) embryos died by E13.5. NCOA1 and NCOA3 are expressed in the labyrinth, and labyrinths of NCOA1(+/-);NCOA3(-/-) and DKO placentas were small compared with wild-type and single-knockout labyrinths. DKO labyrinths exhibited low densities of maternal blood sinuses and fetal capillaries and displayed fetomaternal blood transfusion. At the interface between maternal and fetal circulations, layer I sinusoidal trophoblast giant cells showed a reduced density of microvilli. Layer III syncytiotrophoblasts appeared to accumulate large lipid droplets and have reduced density and deepened invaginations of the intrasyncytial bays. The endothelial layer in DKO labyrinth showed abnormal morphologies and had large lipid droplets. Furthermore, disruption of NCOA1 and NCOA3 increased labyrinth trophoblast proliferation and their progenitor gene expression but decreased their differentiation gene expression. NCOA1 and NCOA3 deficiencies also affected the expression of several genes for placental morphogenesis including TGF?-, peroxisome proliferator-activated receptor-?-, and peroxisome proliferator-activated receptor-?-regulated genes and for glucose transportation including GLUT1 and Cx26. These findings demonstrate that NCOA1 and NCOA3 cooperatively regulate placental morphogenesis and embryo survival.

SUBMITTER: Chen X

PROVIDER: S-EPMC2954639 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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The cooperative function of nuclear receptor coactivator 1 (NCOA1) and NCOA3 in placental development and embryo survival.

Chen Xian X Liu Zhaoliang Z Xu Jianming J

Molecular endocrinology (Baltimore, Md.) 20100804 10

Nuclear receptor coactivator 1 [NCOA1/steroid receptor coactivator (SRC)-1] and NCOA3 (SRC-3/AIB1/ACTR) constitute two thirds of the SRC (steroid receptor coactivator) family. Although in vitro experiments have suggested overlapping functions between NCOA1 and NCOA3, their in vivo functional relationship is poorly understood. In this study, NCOA1 and NCOA3 double knockout mice were generated to determine the compensatory roles of NCOA1 and NCOA3 in development. NCOA1(-/-) mice survived normally, ...[more]

PMID: 20685850

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Project description:Due to the urgent need of new targeting strategies in PCa, AR interacting proteins should be considered. In this study we aimed to test the effect of a long-term knockdown of NCOA1, an AR coactivator, in PCa progression and metastatogenesis and whether NCOA1 could be used as a possible therapeutic target. To test the consequences of NCOA1 knockdown on proliferation, we performed by 3H thymidine incorporation assays revealing a strong reduction in castration resistant MDA PCa 2b and androgen-dependent LNCaP cells, without affecting AR negative PC3 cells. Furthermore, Boyden chamber assays revealed a strong decrease in migration and invasion upon NCOA1 knockdown. Using a cDNA microarray, we identified protein kinase D1 (PRKD1) as one prominent upregulated gene in MDA PCa 2b, which was not seen in PC3 cells. Knockdown of PRKD1 clearly reverted the reduced migratory potential. Moreover, we found phospholipase A2, group7 (PLA2G7) and eukaryotic translation initiation factor 5A2 (EIF5A2), which might be involved in migration of PC3 cells. Further, we can clearly demonstrate that PRKD1 is negatively regulated by the AR/NCOA1 complex. In addition, immunhistochemical staining revealed a strong increase in NCOA1 expression in matched and unmatched patientsâ samples, respectively between normal prostate and primary tumor. Regarding the PRKD1 staining, no final conclusion can be drawn in terms of a tumor suppressor function. Thus, our findings directly associate NCOA1/AR complex with PRKD1 regulation and further suggest NCOA1 as a potential therapeutic target also due to the effect on PC3 cell migration. Cell lines with a stable knockdown of NCOA1 were generated by lentiviral-based transduction of shRNA vectors. For each of the two cell lines MDA and PC3, gene expression profiles were generated for KO and CTRL samples with 3 biological replicates for each. Differential expression analysis was performed by comparing the gene expression estimates between KO and CTRL samples for each cell line.

Dataset Information

The cooperative function of nuclear receptor coactivator 1 (NCOA1) and NCOA3 in placental development and embryo survival.

Publications

The cooperative function of nuclear receptor coactivator 1 (NCOA1) and NCOA3 in placental development and embryo survival.

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