| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Pathology and Laboratory Medicine (S.L.A., L.R.)
Mount Sinai Hospital and Department of Laboratory Medicine and
Pathobiology University of Toronto Toronto, Ontario, Canada M5G
2M9
Department of Physiology and Biophysics (P.R.M.,
A.W.L.) Dalhousie University Halifax, Nova Scotia, Canada B3H
4H7
Department of Medicine (S.E.) Mount Sinai
Hospital and University of Toronto Toronto, Ontario, Canada M5G
2M9
Basic fibroblast growth factor (bFGF; FGF-2) is one of 19 related members of a growth factor family with mitogenic and hormone-regulatory functions. In Xenopus laevis oocytes, a 1.5-kb FGF-2 antisense (GFG) RNA complementary to the third exon and 3'-untranslated region (UTR) of FGF-2 mRNA has been implicated in FGF-2 mRNA editing and stability. The human homolog has been cloned, and we localized this gene by yeast artificial chromosome (YAC), somatic cell, and radiation hybrid panels to the same chromosomal site as FGF-2 (chromosome 4, JO4513 adjacent to D4S430), confirming this as a human endogenous antisense gene. The full-length GFG antisense RNA encodes a 35-kDa protein, which is highly homologous with the MutT family of antimutator nucleosidetriphosphatases (NTPases). We show that human pituitary tumors express FGF-2 and its endogenous antisense partner GFG. While normal pituitary expresses GFG but not FGF-2, pituitary adenomas express FGF-2 and have reduced levels of GFG; aggressive and recurrent adenomas expressed more FGF than GFG mRNA. To examine the effects of this antisense gene in the pituitary, we transfected the pituitary-derived GH4 mammosomatotroph cell line with constructs encoding the full-length human GFG cDNA. Transiently and stably transfected cells expressed the 35-kDa GFG protein that was localized to the cytoplasm. These cells exhibited enhanced PRL expression as documented by transiently transfected PRL-luciferase reporter assay and by endogenous PRL protein. GFG expression in these cells did not alter endogenous FGF-2 expression but increased the proportion of the higher molecular mass 22-kDa form of GH. Moreover, GFG expression inhibited cell proliferation as shown by [3H]thymidine incorporation, proliferating cell nuclear antigen (PCNA) nuclear staining, and cell cycle analysis. We conclude that the GFG-encoded protein has divergent hormone-regulatory and antiproliferative actions in the pituitary that are independent of FGF-2 expression. GFG represents a novel mechanism involved in restraining pituitary tumor cell growth while promoting hormonal activity.
This article has been cited by other articles:
 |
|
 |
|
  X. Zhu, S. L. Asa, and S. Ezzat Fibroblast Growth Factor 2 and Estrogen Control the Balance of Histone 3 Modifications Targeting MAGE-A3 in Pituitary Neoplasia Clin. Cancer Res., April 1, 2008; 14(7): 1984 - 1996. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhu, K. Lee, S. L. Asa, and S. Ezzat Epigenetic Silencing through DNA and Histone Methylation of Fibroblast Growth Factor Receptor 2 in Neoplastic Pituitary Cells Am. J. Pathol., May 1, 2007; 170(5): 1618 - 1628. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Riley, M. A. Mansilla, J. Ma, S. Daack-Hirsch, B. S. Maher, L. M. Raffensperger, E. T. Russo, A. R. Vieira, C. Dode, M. Mohammadi, et al. Impaired FGF signaling contributes to cleft lip and palate PNAS, March 13, 2007; 104(11): 4512 - 4517. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ezzat, L. Zheng, D. Winer, and S. L. Asa Targeting N-Cadherin through Fibroblast Growth Factor Receptor-4: Distinct Pathogenetic and Therapeutic Implications Mol. Endocrinol., November 1, 2006; 20(11): 2965 - 2975. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Ezzat and S L Asa The molecular pathogenetic role of cell adhesion in endocrine neoplasia J. Clin. Pathol., November 1, 2005; 58(11): 1121 - 1125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Barclay, A. W. Li, L. Geldenhuys, M. Baguma-Nibasheka, G. A. Porter, P. J. Veugelers, P. R. Murphy, and A. G. Casson Basic Fibroblast Growth Factor (FGF-2) Overexpression Is a Risk Factor for Esophageal Cancer Recurrence and Reduced Survival, which Is Ameliorated by Coexpression of the FGF-2 Antisense Gene Clin. Cancer Res., November 1, 2005; 11(21): 7683 - 7691. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Werner and A. Berdal Natural antisense transcripts: sound or silence? Physiol Genomics, October 17, 2005; 23(2): 125 - 131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ezzat, S. Yu, and S. L. Asa The Zinc Finger Ikaros Transcription Factor Regulates Pituitary Growth Hormone and Prolactin Gene Expression through Distinct Effects on Chromatin Accessibility Mol. Endocrinol., April 1, 2005; 19(4): 1004 - 1011. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ezzat, L. Zheng, and S. L. Asa Pituitary Tumor-Derived Fibroblast Growth Factor Receptor 4 Isoform Disrupts Neural Cell-Adhesion Molecule/N-Cadherin Signaling to Diminish Cell Adhesiveness: A Mechanism Underlying Pituitary Neoplasia Mol. Endocrinol., October 1, 2004; 18(10): 2543 - 2552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Gomez and J. A. Balsa Autocrine/Paracrine Action of Pituitary Vasoactive Intestinal Peptide on Lactotroph Hyperplasia Induced by Estrogen Endocrinology, October 1, 2003; 144(10): 4403 - 4409. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ezzat, S. Yu, and S. L. Asa Ikaros Isoforms in Human Pituitary Tumors: Distinct Localization, Histone Acetylation, and Activation of the 5' Fibroblast Growth Factor Receptor-4 Promoter Am. J. Pathol., September 1, 2003; 163(3): 1177 - 1184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Mihalich, M. Reina, S. Mangioni, E. Ponti, L. Alberti, P. Vigano, M. Vignali, and A. M. Di Blasio Different Basic Fibroblast Growth Factor and Fibroblast Growth Factor-Antisense Expression in Eutopic Endometrial Stromal Cells Derived from Women with and without Endometriosis J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2853 - 2859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yu, L. Zheng, S. L. Asa, and S. Ezzat Fibroblast growth factor receptor 4 (FGFR4) mediates signaling to the prolactin but not the FGFR4 promoter Am J Physiol Endocrinol Metab, September 1, 2002; 283(3): E490 - E495. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
