The establishment and maintenance of pregnancy requires the coordinated hormonal regulation of corpus luteum (CL) function. Extensive investigations from our laboratory have defined the action and interaction of estradiol (E) and prolactin (PRL) and have led to the recent discovery that PRL signaling through the short form of the PRL receptor (PRLRS) has a severe impact on the ovary, causing follicular degeneration and premature ovarian failure. Because of our observation that the expression of PRLRS in the ovaries of PRL null mice leads to inhibition of Foxo3a and GALT, 2 proteins whose deletion/mutation causes similar premature ovarian failure, we propose in the first specific aim to determine whether PRL acting through PRLRS prevents the expression of Foxo3a which normally stimulates GALT transcriptional activity. Absence of Foxo3 then leads to inhibition of GALT and an increase in galactose and its metabolites, causing galactose toxicity and cell death in granulosa and oocytes. We have also discovered that PRLRS associates with and, when activated by PRL, causes the phosphorylation of a newly discovered enzyme responsible for E synthesis in the CL that we named PRAP/17BHSD-7. This is the first demonstration that direct association of a membrane bound receptor with a steroidogenic enzyme can lead to enzyme phosphorylation. This association may also prevent PRL signaling through PRLRS. The significance of such phosphorylation, and the importance of PRAP/17aHSD-7 in luteal E production, its regulation and its role in the maintenance of pregnancy will be investigated using both cell lines and PRAP/17aHSD-7 null mice that we propose to generate.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD011119-28
Application #
7231004
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Taymans, Susan
Project Start
1978-01-01
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
28
Fiscal Year
2007
Total Cost
$286,589
Indirect Cost
Name
University of Illinois at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Olafsson, Sigurast; Whittington, Dale; Murray, Jason et al. (2017) Fast and sensitive HPLC-MS/MS method for direct quantification of intracellular deoxyribonucleoside triphosphates from tissue and cells. J Chromatogr B Analyt Technol Biomed Life Sci 1068-1069:90-97
Le, Jamie A; Wilson, Heather M; Shehu, Aurora et al. (2012) Generation of mice expressing only the long form of the prolactin receptor reveals that both isoforms of the receptor are required for normal ovarian function. Biol Reprod 86:86
Shehu, Aurora; Albarracin, Constance; Devi, Y Sangeeta et al. (2011) The stimulation of HSD17B7 expression by estradiol provides a powerful feed-forward mechanism for estradiol biosynthesis in breast cancer cells. Mol Endocrinol 25:754-66
Le, J A; Wilson, H M; Shehu, A et al. (2011) Prolactin activation of the long form of its cognate receptor causes increased visceral fat and obesity in males as shown in transgenic mice expressing only this receptor subtype. Horm Metab Res 43:931-7
Devi, Y Sangeeta; Seibold, Anita M; Shehu, Aurora et al. (2011) Inhibition of MAPK by prolactin signaling through the short form of its receptor in the ovary and decidua: involvement of a novel phosphatase. J Biol Chem 286:7609-18
Bachelot, Anne; Beaufaron, Julie; Servel, Nathalie et al. (2009) Prolactin independent rescue of mouse corpus luteum life span: identification of prolactin and luteinizing hormone target genes. Am J Physiol Endocrinol Metab 297:E676-84
Devi, Y Sangeeta; Shehu, Aurora; Stocco, Carlos et al. (2009) Regulation of transcription factors and repression of Sp1 by prolactin signaling through the short isoform of its cognate receptor. Endocrinology 150:3327-35
Devi, Y Sangeeta; Shehu, Aurora; Halperin, Julia et al. (2009) Prolactin signaling through the short isoform of the mouse prolactin receptor regulates DNA binding of specific transcription factors, often with opposite effects in different reproductive issues. Reprod Biol Endocrinol 7:87
Shehu, Aurora; Mao, Jifang; Gibori, Gil B et al. (2008) Prolactin receptor-associated protein/17beta-hydroxysteroid dehydrogenase type 7 gene (Hsd17b7) plays a crucial role in embryonic development and fetal survival. Mol Endocrinol 22:2268-77
Halperin, Julia; Devi, Sangeeta Y; Elizur, Shai et al. (2008) Prolactin signaling through the short form of its receptor represses forkhead transcription factor FOXO3 and its target gene galt causing a severe ovarian defect. Mol Endocrinol 22:513-22

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