Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK031206-20
Application #
6615823
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Tondravi, Mehrdad M
Project Start
1983-08-01
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
20
Fiscal Year
2003
Total Cost
$349,992
Indirect Cost

  Institution

Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390

  Publications

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
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
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
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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