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Molecular and Cellular Biology, October 2005, p. 8824-8833, Vol. 25, No. 20
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.20.8824-8833.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

O2 Enhancement of Human Trophoblast Differentiation and hCYP19 (Aromatase) Gene Expression Are Mediated by Proteasomal Degradation of USF1 and USF2

Bing Jiang1 and Carole R. Mendelson1,2*

Departments of Obstetrics and Gynecology,1 Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas2

Received 7 February 2005/ Returned for modification 31 March 2005/ Accepted 25 July 2005

When cultured in 20% O2, human cytotrophoblasts fuse to form the syncytiotrophoblast with marked induction of hCYP19 (aromatase) gene expression. When cultured in 2% O2, cytotrophoblast fusion and induced hCYP19 expression are prevented. These effects of hypoxia are mediated by increased expression of mammalian achaete/scute homologue-2 (Mash-2), which increases levels of upstream stimulatory factors 1 and 2 (USF1/2) and their binding as heterodimers to E-boxes surrounding the hCYP19 promoter. In studies to define mechanisms for O2 regulation of syncytiotrophoblast differentiation, we found that hypoxia and overexpression of Mash-2 markedly increased cyclin B1 levels in cultured trophoblasts and the proportion of cells at the G2/M transition. Unlike USF proteins, USF1/2 mRNA levels are unaffected by O2 tension. To determine whether increased O2 might enhance proteasomal degradation of USF1/2, human trophoblasts were cultured in 2% or 20% O2 with or without proteasome inhibitors. In cells cultured in 20% O2, proteasome inhibitors increased USF1/2 protein levels and blocked spontaneous induction of hCYP19 expression, cell fusion, and differentiation. Like hypoxia, inhibitory effects of proteasome inhibitors on hCYP19 expression were mediated by increased binding of USF1/2 to the E-boxes. In human trophoblast cells cultured in 20% O2, increased polyubiquitylation of USF1/2 proteins was observed. Thus, early in gestation when the placenta is relatively hypoxic, increased USF1/2 may block trophoblast differentiation and hCYP19 gene expression. In the second trimester, increased O2 tension promotes proteasomal degradation of USF1/2, resulting in syncytiotrophoblast differentiation and induction of hCYP19 expression.

* Corresponding author. Mailing address: Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038. Phone: (214) 648-2944. Fax: (214) 648-3214. E-mail: carole.mendelson{at}utsouthwestern.edu.

Molecular and Cellular Biology, October 2005, p. 8824-8833, Vol. 25, No. 20
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.20.8824-8833.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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