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Molecular and Cellular Biology, December 2004, p. 10661-10669, Vol. 24, No. 24
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.24.10661-10669.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Peroxisome Proliferator-Activated Receptor {gamma} Controls Muc1 Transcription in Trophoblasts

Tali Shalom-Barak,1 Jill M. Nicholas,1 Yongxu Wang,2 Xiaowen Zhang,1 Estelita S. Ong,2,3 Timothy H. Young,1 Sandra J. Gendler,4 Ronald M. Evans,2,3 and Yaacov Barak*

The Jackson Laboratory, Bar Harbor, Maine,1 ,2 Howard Hughes Medical Institute and The Salk Institute, La Jolla, California,3 Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, Arizona4

Received 30 June 2004/ Returned for modification 26 July 2004/ Accepted 20 September 2004

The nuclear receptor peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) is essential for placental development. Here, we show that the mucin gene Muc1 is a PPAR{gamma} target, whose expression is lost in PPAR{gamma} null placentas. During differentiation of trophoblast stem cells, PPAR{gamma} is strongly induced, and Muc1 expression is upregulated by the PPAR{gamma} agonist rosiglitazone. Muc1 promoter is activated strongly and specifically by liganded PPAR{gamma} but not PPAR{alpha} or PPAR{delta}. A PPAR binding site (DR1) in the proximal Muc1 promoter acts as a basal silencer in the absence of PPAR{gamma}, and its cooperation with a composite upstream enhancer element is both necessary and sufficient for PPAR{gamma}-dependent induction of Muc1. In the placenta, MUC1 protein is localized exclusively to the apical surface of the labyrinthine trophoblast around maternal blood sinuses, resembling its luminal localization on secretory epithelia. Last, variably penetrant maternal blood sinus dilation in Muc1-deficient placentas suggests that Muc1 regulation by PPAR{gamma} contributes to normal placental development but also that the essential functions of PPAR{gamma} in the organ are mediated by other targets.

* Corresponding author. Mailing address: The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609. Phone: (207) 288-6704. Fax: (207) 288-6077. E-mail: ybarak{at}jax.org.

Molecular and Cellular Biology, December 2004, p. 10661-10669, Vol. 24, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.24.10661-10669.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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