The objective of the proposed research is to define cis-acting elements and transcription factors that mediate CYP19 expression in the appropriate tissue-/cell-specific and developmentally regulated manners. Transgenic mice will be created carrying chimeric reporter gene constructs comprised of DNA flanking placenta-specific exon I.1, ovary/testis-specific exon II, and adipose/fetal liver-specific expression. The molecular basis for 'promoter switching' will be analyzed in transgenic mice bearing endocrine-responsive mammary and liver tumors. Transfected human trophoblasts in primary culture will be used to define the cis-acting elements that are required for syncytiotrophoblast-specific CYP19 promoter I.1 expression. Once gene regulatory elements are defined, they will be used to isolate cDNAs encoding transcription factors that mediate syncytiotrophoblast-specific CYP19 gene expression. It is proposed to continue to characterize transcription factors that mediate syncytiotrophoblast differentiation and its regulation by hypoxia/O2 and to define their expression in preeclampsia.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Biochemical Endocrinology Study Section (BCE)
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Tondravi, Mehrdad M
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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Muralimanoharan, Sribalasubashini; Kwak, Youn-Tae; Mendelson, Carole R (2018) Redox-Sensitive Transcription Factor NRF2 Enhances Trophoblast Differentiation via Induction of miR-1246 and Aromatase. Endocrinology 159:2022-2033
Zhang, Ming; Muralimanoharan, Sribalasubashini; Wortman, Alison C et al. (2016) Primate-specific miR-515 family members inhibit key genes in human trophoblast differentiation and are upregulated in preeclampsia. Proc Natl Acad Sci U S A 113:E7069-E7076
Luo, Yanmin; Kumar, Premlata; Chen, Chien-Cheng et al. (2014) Estrogen-related receptor ? serves a role in blood pressure homeostasis during pregnancy. Mol Endocrinol 28:965-75
Kumar, Premlata; Luo, Yanmin; Tudela, Carmen et al. (2013) The c-Myc-regulated microRNA-17~92 (miR-17~92) and miR-106a~363 clusters target hCYP19A1 and hGCM1 to inhibit human trophoblast differentiation. Mol Cell Biol 33:1782-96
Mendelson, Carole R (2013) GRTH: a key to understanding androgen-mediated germ cell signaling. Endocrinology 154:1967-9
Luo, Yanmin; Kumar, Premlata; Mendelson, Carole R (2013) Estrogen-related receptor ? (ERR?) regulates oxygen-dependent expression of voltage-gated potassium (K+) channels and tissue kallikrein during human trophoblast differentiation. Mol Endocrinol 27:940-52
Chen, Chien-Cheng; Hardy, Daniel B; Mendelson, Carole R (2011) Progesterone receptor inhibits proliferation of human breast cancer cells via induction of MAPK phosphatase 1 (MKP-1/DUSP1). J Biol Chem 286:43091-102
Kumar, Premlata; Mendelson, Carole R (2011) Estrogen-related receptor gamma (ERRgamma) mediates oxygen-dependent induction of aromatase (CYP19) gene expression during human trophoblast differentiation. Mol Endocrinol 25:1513-26
Kumar, Premlata; Kamat, Amrita; Mendelson, Carole R (2009) Estrogen receptor alpha (ERalpha) mediates stimulatory effects of estrogen on aromatase (CYP19) gene expression in human placenta. Mol Endocrinol 23:784-93
Bukulmez, Orhan; Hardy, Daniel B; Carr, Bruce R et al. (2008) Androstenedione up-regulation of endometrial aromatase expression via local conversion to estrogen: potential relevance to the pathogenesis of endometriosis. J Clin Endocrinol Metab 93:3471-7

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