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This Article Full Text Full Text (PDF) All Versions of this Article: 78/6/1038    most recent biolreprod.107.066340v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Sriraman, V. Articles by Richards, J. S. PubMed PubMed Citation Articles by Sriraman, V. Articles by Richards, J. S. Agricola Articles by Sriraman, V. Articles by Richards, J. S.

Regulated Expression of ADAM8 (a Disintegrin and Metalloprotease Domain 8) in the Mouse Ovary: Evidence for a Regulatory Role of Luteinizing Hormone, Progesterone Receptor, and Epidermal Growth Factor-Like Growth Factors¹

Institute of Genetechnology/Microbiology,³ University of Bielefeld, D-33501 Bielefeld, Germany Department of Biochemistry,⁴ King's College London, London SE1 9NH, United Kingdom Biochemical Institute,⁵ University of Kiel, 24098 Kiel, Germany N.V. Organon,⁶ 5340 BH Oss, The Netherlands Department of Molecular and Cellular Biology,⁷ Baylor College of Medicine, Houston, Texas 77030

ABSTRACT

ADAM8 (a disintegrin and metalloprotease domain 8) is expressed in immune, neuronal, and bone progenitor cells and is thought to be involved in the tissue-remodeling process. Microarray analyses indicate that Adam8 is a potential target of the progesterone receptor (Pgr) in murine ovary. Further studies document that Adam8 mRNA and protein are expressed in granulosa cells and cumulus cells of periovulatory follicles whereas expression is significantly reduced in Pgr null mice that fail to ovulate. There is a reduced expression in granulosa cells from cultured, in vitro ovulated follicles exposed to inhibitors of progesterone or epidermal growth factor signaling while epiregulin induced its expression in the absence of hCG. In vitro studies with primary mouse granulosa cells document that Adam8 is induced in response to forskolin (Fo) and phorbol ester (PMA) or Fo and Amphiregulin treatment. To understand the transcriptional regulation of the Adam8, we amplified 1 kb of the mouse Adam8 promoter by PCR and subcloned it into a pGL3-luciferase reporter construct. The Adam8 promoter-luciferase constructs are induced by Fo and PMA treatment after transfection into rat granulosa cells, and cotransfection with a PGR-A expression vector further augment basal and Fo/PMA inducibility. Site-specific mutations within the –615/+50 promoter document that a GC-rich region, NF-1 (nuclear factor-1) site, and putative TATA box are critical for Adam8 promoter activation by Fo/PMA. Thus, ADAM8 is expressed in a stage-specific manner and is hormonally regulated in ovulating follicles by the coordinate actions of LH and PGR. To our knowledge, ADAM8 is the first member of the ADAM family shown to be hormonally regulated.

luteinizing hormone, ovary, ovulation, progesterone receptor

¹Supported by NIH grants HD16229 and HD07495 (SCCPIR) (J.S.R.) and by the King's College (J.W.B.). V.S. is supported in part by the NICHD and Office of Research on Women's Health as a Building Interdisciplinary Research Careers in Women's Health Scholar K12HD052023 and ASRM/Organon grant.

Correspondence: ²Venkataraman Sriraman, Department of Internal Medicine,³ Division of Endocrinology, University of Texas Medical Branch, Galveston, Texas 77555. FAX: 409 772 8709; e-mail: vesriram{at}utmb.edu