Medical Student Research Fellowship for Summer 2002

Mentor: Carole R. Mendelson, Ph.D.
Department: Biochemistry
Room number: K3.104
Mail Code: 9038
Phone number: 214-648-2944
E-mail: cmende@biochem.swmed.edu
Project title: Mechanisms in Tissue-Specific Regulation of Estrogen Biosynthesis in Humans

Human subjects IRB approved project number (where applicable): 1076 02000

Animal subjects IRB approved project number (where applicable): 0057-01-03-3

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) Basic

Brief Description of Project:
Estrogens play an essential role in the development of sexually dimorphic anatomical, functional and behavioral characteristics that are essential for reproduction in vertebrates. In addition to its well-characterized effects on reproduction, estrogen acts to promote growth, migration, differentiation and survival of neurons, and also affects plasticity of neurons and glial cells in many areas of the brain. Estrogen also has been implicated in the pathophysiology of several disease states, including breast and endometrial cancer. The synthesis of estrogens from C19-steroids is catalyzed by the aromatase enzyme complex, which contains a unique cytochrome P450 (aromatase P450, the product of the CYP19 gene), expressed exclusively in estrogen-producing cells. CYP19 expression is restricted to the gonads and brain in most vertebrates. However in humans, there is a much broader tissue distribution, which also includes placenta, adipose tissue, bone and various fetal tissues. We have observed that CYP19 gene expression in human tissues is regulated by use of different tissue-specific promoters that lie upstream of unique first exons encoding 5'-untranslated regions of the aromatase mRNAs. To identify the genetic elements and transcription factors that mediate tissue- and cell-specific expression of the human CYP19 gene and lead to its enhanced expression in adipose stromal cells surrounding breast carcinomas, are utilizing transgenic mice and transfected estrogen-producing cells. Studies will be carried out this summer to further define genetic response elements and transcription factors within selected promoter regions that mediate tissue-specific and hormonally regulated CYP19 gene expression.

Previous Research Activities or Publications with Medical Students:
Molsberry, R.L., Carr, B.R., Mendelson, C.R., and Simpson, E.R. hCG binding to human fetal testes as a function of gestational age. J. Clin. Endocrinol. Metab. 55:791-794, 1982.
Ng, V.L., Herndon, V.L., Mendelson, C.R., and Snyder, J.M. Characterization of rabbit surfactant associated proteins. Biochim. Biophys. Acta 754:218-226, 1983.
Anderson, C.M., and Mendelson, C.R. Regulation of the synthesis of cholesterol side chain cleavage cytochrome P-450 and adrenodoxin in rat Leydig cells. Ann. N.Y. Acad. Sci. 438:259-268, 1984.
Durham, C.R., Zu, H., Masters, B.S.S., Simpson, E.R., and Mendelson, C.R. Regulation of aromatase in rat granulosa cells: Indication of synthesis of NADPH-cytochrome P-450 reductase by FSH and dibutyryl cyclic AMP. Mol. Cell. Endocrinol. 40:211-219, 1985.
Anderson, C.M., and Mendelson, C.R. Regulation of steroidogenesis in rat Leydig cells in culture: Effect of human chorionic gonadotropin and dibutyryl cyclic AMP on the synthesis of cholesterol side-chain cleavage and adrenodoxin. Arch. Biochem. Biophys. 238:378-387, 1985.
Lanoux, M.J., Cleland, W.H., Mendelson, C.R., Carr, B.R., and Simpson, E.R. Factors affecting the conversion of androstenedione to estrogens by human fetal hepatocytes in monolayer culture. Endocrinology 117:361-368, 1985.
Anderson, C.M., and Mendelson, C.R. Developmental and hormonal regulation of cholesterol side chain cleavage cytochrome P-450 in the fetal rabbit testis. Mol. Cell. Endocrinol. 55:121-130, 1988.
Young, P.P., and Mendelson, C.R. A CRE-like element plays an essential role in cyclic AMP regulation of the human surfactant protein-A2 (SP-A2) gene. Am. J. Physiol.: Lung Cell. Mol. Physiol., 271:L287-L299, 1996.
Young, P.P., and Mendelson, C.R. A GT box is essential for basal and cyclic AMP regulation of the human SP?A2 gene in alveolar type II cells: Evidence for the binding of lung nuclear factors distinct from Sp1. Mol. Endocrinol 11:1082-1093, 1997.
Muenster, M.R., Gao E., Wang, L., Smith M.E., Alcorn, J.L., and Mendelson, C.R. Role of transcription factor BTEB2 in developmental and cyclic AMP regulation of surfactant protein?A (SP?A) gene expression. The Endocrine Society Annual Meeting, 1998, oral presentation and travel grant award.
Mendelson, C.R., Young, P.P, Michael, L.F., Alcorn, J.L., and Gao, E.E. Transcriptional regulation of the surfactant protein-A gene. Chest, 111:96S-104S, 1997.
Mendelson, C.R., Young, P.P., Michael, L.F., Gao, E., and Alcorn, J.L. The surfactant protein A gene and its regulation. In: Lung Surfactant: Cellular and Molecular Processing. (Rooney, S.A., ed.) pp. 47-73, R.G. Landes, Co., 1998.
Mendelson, C.R., Gao, E., Li, J., Young, P.P., Michael, L.F., and Alcorn, J.L. Regulation of expression of surfactant protein?A. Biochim. Biophys. Acta 1408:132-149, 1998.
Mendelson, C.R., Michael, L.F., Young, P.P., Li, J., and Alcorn, J.L. Cyclic AMP and glucocorticoid regulation of surfactant protein-A gene expression. In: Endocrinology of the Lung: Development and Surfactant Synthesis (Mendelson, C.R., ed.), Humana Press, pp. 59-80, 2000.

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