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      Pathology, Pathogenesis and Therapy of Growth Hormone (GH)-producing Pituitary Adenomas: Technical Advances in Histochemistry and Their Contribution

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          Abstract

          Growth hormone (GH)-producing adenomas (GHomas) are one of the most frequently-occurring pituitary adenomas. Differentiation of hormone-producing cells in the pituitary gland is regulated by transcription factors and co-factors. The transcription factors include Pit-1, Prop-1, NeuroD1, Tpit, GATA-2, SF-1. Aberrant expression of transcription factors such as Pit-1 results in translineage expression of GH in adrenocorticotropic hormone-producing adenomas (ACTHomas). This situation has been substantiated by GFP-Pit-1 transfection expression in the AtT20 cell line. Experimentally, GHomas have been induced in GH-releasing hormone (GHRH) or Prop-1 transgenic animals. Immunohistochemical detection of somatostatin receptor (SSTR2a) has recently emphasized their role in the response of GHomas to somatostatin analogue therapy. In this review, the advances in technology and their contribution to cell biology and medical practice are discussed.

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          Most cited references26

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          Regulation and function of somatostatin receptors.

          This review summarizes the latest advances that have been made to elucidate the somatostatinergic system in respect to somatostatin receptor evolution, the development of receptor agonists/antagonists, receptor regulation, signal transduction, effects on cell proliferation, receptor-receptor or receptor-protein interactions and receptor function.
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            Persistent Prop1 expression delays gonadotrope differentiation and enhances pituitary tumor susceptibility.

            The 'paired'-like homeodomain transcription factor Prop1 is essential for the expansion of the pituitary primordia and for the differentiation and/or function of the hormone-producing cells of the anterior pituitary gland. Prop1 expression is normally extinguished before transcription of most differentiation markers is initiated. We report that constitutive expression of Prop1 interferes with anterior pituitary cell differentiation and increases the susceptibility for pituitary tumors. The terminal differentiation of pituitary gonadotropes is delayed, resulting in transient hypogonadism and a delay in the onset of puberty. Thyrotrope differentiation occurs normally, but thyrotrope function is impaired resulting in mild hypothyroidism. Aged mice exhibit defects consistent with misregulation of pituitary cell proliferation, including adenomatous hyperplasia with the formation of Rathke's cleft cysts and tumors. Thus, silencing Prop1 is important for normal pituitary development and function. These data suggest that gain-of-function mutations in PROP1 could contribute to the most common human pituitary endocrinopathies and tumors.
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              FOXL2 in the pituitary: molecular, genetic, and developmental analysis.

              FOXL2 is a forkhead transcription factor expressed in the eye, ovary, and pituitary gland. Loss of function mutations in humans and mice confirm a functional role for FOXL2 in the eye and ovary, but its role in the pituitary is not yet defined. We report that FOXL2 colocalizes with the glycoprotein hormone alpha-subunit (alphaGSU) in quiescent cells of the mouse pituitary from embryonic d 11.5 through adulthood. FOXL2 is expressed in essentially all gonadotropes and thyrotropes and a small fraction of prolactin-containing cells during pregnancy, but not somatotropes or corticotropes. The coincident expression patterns of FOXL2 and alphaGSU suggested that the alphaGSU gene (Cga) is a downstream target of FOXL2. We demonstrate that FOXL2 regulates mouse Cga transcription in gonadotrope-derived (alphaT3-1, LbetaT2), thyrotrope-derived (alphaTSH) and heterologous (CV-1) cells in a context-dependent manner. In addition, a FOXL2-VP16 fusion protein is sufficient to stimulate ectopic Cga expression in transgenic animals. Normal FOXL2 expression requires the transcription factors Lhx3 and Lhx4 but not of Prop1. Thus, FOXL2 expression is affected by mutations in early pituitary developmental regulatory genes, and its expression precedes that of genes necessary for gonadotrope-specific development such as Egr1 and Sf1 (Nr5a1). These data place FOXL2 in the hierarchy of pituitary developmental control and suggest a role in regulation of Cga gene expression.
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                Author and article information

                Journal
                Acta Histochem Cytochem
                AHC
                Acta Histochemica et Cytochemica
                Japan Society of Histochemistry and Cytochemistry (Tokyo, Japan )
                0044-5991
                1347-5800
                29 August 2009
                11 August 2009
                : 42
                : 4
                : 95-104
                Affiliations
                [1 ]Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara-city, Kanagawa 259–1193, Japan
                [2 ]Department of Neurosurgery, Nippon Medical School, 1–1–5 Sendagi, Bunkyo-ku, Tokyo 113–8603, Japan
                [3 ]Division of Diabetes, Metabolism and Endocrinology, Jikei University School of Medicine, 3–25–8 Nishishinbashi, Minato-ku, Tokyo 105–8461, Japan
                Author notes
                Correspondence to: Robert Yoshiyuki Osamura, M.D., Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara-city, Kanagawa 259–1193, Japan. E-mail: osamura@ 123456is.icc.u-tokai.ac.jp
                Article
                AHC09004
                10.1267/ahc.09004
                2742723
                19759870
                69c0b058-df4e-4498-86fd-d7aecd97410a
                © 2009 The Japan Society of Histochemistry and Cytochemistry

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 January 2009
                : 3 June 2009
                Categories
                Regular Article

                Clinical chemistry
                cell lineage,pituitary hormones,pituitary adenoma,transcription factor,functional differentiation

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