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Molecular Endocrinology Vol. 4, No. 4 597-603
doi:10.1210/mend-4-4-597
Copyright © 1990 by the Endocrine Society.
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Cell Lines of the Pituitary Gonadotrope Lineage Derived by Targeted Oncogenesis in Transgenic Mice

Jolene J. Windle*, Richard I. Weiner and Pamela L. Mellon

Regulatory Biology Laboratory, The Salk Institute La Jolla, California 92037
Reproductive Endocrinology Center, University of California San Francisco, California 94143

Address requests for reprints to: Pamela L. Mellon, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037.

Abstract

Study of the molecular and cellular biology of the gonadotropin hormones would be greatly facilitated by the availability of immortalized anterior pituitary gonadotrope cell lines. We directed expression of the simian virus-40 (SV40) T-antigen (Tag) oncogene to specific cells in the anterior pituitary of transgenic mice using the promoter/enhancer region from the human glycoprotein hormone {alpha}-subunit gene. Transgenic mice carrying this fusion gene developed anterior pituitary tumors. Clonal cell lines established from these tumors express the endogenous mouse {alpha}-subunit gene and synthesize and secrete a-subunit protein. However, they do not express β-subunit genes. Alpha-subunit mRNA is induced by GnRH in a dose- and time-dependent manner, but is not regulated by TRH. Thus, we have targeted tumorigenesis in transgenic mice to anterior pituitary cells of the gonadotrope lineage to immortalize this specific endocrine cell while maintaining several highly differentiated functions unique to gonadotropes.

FOOTNOTES

This work was supported by NIH Grant HD-20377 and March of Dimes Grant 1–1182 (to P.L.M.) and NIH Grant HD-08924 (to R.I.W.).

* Supported by the American Cancer Society and the J. Aron Charitable Foundation.

Received for publication November 17, 1989. Revision received January 16, 1990. Accepted for publication January 16, 1990.




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Gonadotropin-Releasing Hormone Receptor Activation of Extracellular Signal-Regulated Kinase and Tyrosine Kinases in Transfected GH3 Cells and in {alpha}T3-1 Cells
Endocrinology, September 1, 2000; 141(9): 3087 - 3097.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
R. Grosse, S. Roelle, A. Herrlich, J. Hohn, and T. Gudermann
Epidermal Growth Factor Receptor Tyrosine Kinase Mediates Ras Activation by Gonadotropin-releasing Hormone
J. Biol. Chem., April 14, 2000; 275(16): 12251 - 12260.
[Abstract] [Full Text] [PDF]

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 J. Histochem. Cytochem.Home page
R. Y. Osamura, S. Tahara, R. Kurotani, N. Sanno, A. Matsuno, and A. Teramoto
Contributions of Immunohistochemistry and In Situ Hybridization to the Functional Analysis of Pituitary Adenomas
J. Histochem. Cytochem., April 1, 2000; 48(4): 445 - 458.
[Abstract] [Full Text]

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 J. Biol. Chem.Home page
R. Grosse, A. Schmid, T. Schoneberg, A. Herrlich, P. Muhn, G. Schultz, and T. Gudermann
Gonadotropin-releasing Hormone Receptor Initiates Multiple Signaling Pathways by Exclusively Coupling to Gq/11 Proteins
J. Biol. Chem., March 24, 2000; 275(13): 9193 - 9200.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
D. J. Glenn and R. A. Maurer
MRG1 Binds to the LIM Domain of Lhx2 and May Function as a Coactivator to Stimulate Glycoprotein Hormone alpha -Subunit Gene Expression
J. Biol. Chem., December 17, 1999; 274(51): 36159 - 36167.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
M. W. Wolfe
The Equine Luteinizing Hormone {beta}-Subunit Promoter Contains Two Functional Steroidogenic Factor-1 Response Elements
Mol. Endocrinol., September 1, 1999; 13(9): 1497 - 1510.
[Abstract] [Full Text]

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 Biol. Reprod.Home page
G. B. Call and M. W. Wolfe
Gonadotropin-Releasing Hormone Activates the Equine Luteinizing Hormone {beta} Promoter Through a Protein Kinase C/Mitogen-Activated Protein Kinase Pathway
Biol Reprod, September 1, 1999; 61(3): 715 - 723.
[Abstract] [Full Text]

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 EndocrinologyHome page
E. S. W. Ngan, P. K. W. Cheng, P. C. K. Leung, and B. K. C. Chow
Steroidogenic Factor-1 Interacts with a Gonadotrope-Specific Element within the First Exon of the Human Gonadotropin-Releasing Hormone Receptor Gene to Mediate Gonadotrope-Specific Expression
Endocrinology, June 1, 1999; 140(6): 2452 - 2462.
[Abstract] [Full Text]

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 EndocrinologyHome page
H. G. Sutton, A. Fusco, and G. A. Cornwall
Cystatin-Related Epididymal Spermatogenic Protein Colocalizes with Luteinizing Hormone-{beta} Protein in Mouse Anterior Pituitary Gonadotropes
Endocrinology, June 1, 1999; 140(6): 2721 - 2732.
[Abstract] [Full Text]

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 Mol. Endocrinol.Home page
M. W. Wolfe and G. B. Call
Early Growth Response Protein 1 Binds to the Luteinizing Hormone-{beta} Promoter and Mediates Gonadotropin-Releasing Hormone-Stimulated Gene Expression
Mol. Endocrinol., May 1, 1999; 13(5): 752 - 763.
[Abstract] [Full Text]

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 EndocrinologyHome page
C. T. Albarracin, M. P. Frosch, and W. W. Chin
The Gonadotropin-Releasing Hormone Receptor Gene Promoter Directs Pituitary-Specific Oncogene Expression in Transgenic Mice
Endocrinology, May 1, 1999; 140(5): 2415 - 2421.
[Abstract] [Full Text]

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 Mol. Cell. Biol.Home page
J. J. Tremblay and J. Drouin
Egr-1 Is a Downstream Effector of GnRH and Synergizes by Direct Interaction with Ptx1 and SF-1 To Enhance Luteinizing Hormone beta  Gene Transcription
Mol. Cell. Biol., April 1, 1999; 19(4): 2567 - 2576.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
B. R. White, D. L. Duval, J. M. Mulvaney, M. S. Roberson, and C. M. Clay
Homologous Regulation of the Gonadotropin-Releasing Hormone Receptor Gene Is Partially Mediated by Protein Kinase C Activation of an Activator Protein-1 Element
Mol. Endocrinol., April 1, 1999; 13(4): 566 - 577.
[Abstract] [Full Text]

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 EndocrinologyHome page
M. S. Roberson, T. Zhang, H. L. Li, and J. M. Mulvaney
Activation of the p38 Mitogen-Activated Protein Kinase Pathway by Gonadotropin-Releasing Hormone
Endocrinology, March 1, 1999; 140(3): 1310 - 1318.
[Abstract] [Full Text]

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 Endocr. Rev.Home page
J. J. Evans
Modulation of Gonadotropin Levels by Peptides Acting at the Anterior Pituitary Gland
Endocr. Rev., February 1, 1999; 20(1): 46 - 67.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
E. J. Lee, L. M. Anderson, B. Thimmapaya, and J. L. Jameson
Targeted Expression of Toxic Genes Directed by Pituitary Hormone Promoters: A Potential Strategy for Adenovirus-Mediated Gene Therapy of Pituitary Tumors
J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 786 - 794.
[Abstract] [Full Text]

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 Mol. Endocrinol.Home page
D. A. Schreihofer, E. M. Resnick, A. Y. Soh, and M. A. Shupnik
Transcriptional Regulation by a Naturally Occurring Truncated Rat Estrogen Receptor (ER), Truncated ER Product-1 (TERP-1)
Mol. Endocrinol., February 1, 1999; 13(2): 320 - 329.
[Abstract] [Full Text]

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 EndocrinologyHome page
S. K. Mahata, M. Mahata, C. V. Livsey, H.-H. Gerdes, W. B. Huttner, and D. T. O’Connor
Neuroendocrine Cell Type-Specific and Inducible Expression of the Secretogranin II Gene: Crucial Role of Cyclic Adenosine Monophosphate and Serum Response Elements
Endocrinology, February 1, 1999; 140(2): 739 - 749.
[Abstract] [Full Text]

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 EndocrinologyHome page
S. Nelson, R. D. Horvat, J. Malvey, D. A. Roess, B. G. Barisas, and C. M. Clay
Characterization of an Intrinsically Fluorescent Gonadotropin-Releasing Hormone Receptor and Effects of Ligand Binding on Receptor Lateral Diffusion
Endocrinology, February 1, 1999; 140(2): 950 - 957.
[Abstract] [Full Text]

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 J. Biol. Chem.Home page
E. R. Norwitz, G. R. Cardona, K.-H. Jeong, and W. W. Chin
Identification and Characterization of the Gonadotropin-releasing Hormone Response Elements in the Mouse Gonadotropin-releasing Hormone Receptor Gene
J. Biol. Chem., January 8, 1999; 274(2): 867 - 880.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
L. M. Halvorson, U. B. Kaiser, and W. W. Chin
The Protein Kinase C System Acts through the Early Growth Response Protein 1 to Increase LH{beta} Gene Expression in Synergy with Steroidogenic Factor-1
Mol. Endocrinol., January 1, 1999; 13(1): 106 - 116.
[Abstract] [Full Text]

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 Mol. Endocrinol.Home page
L. L. Heckert, M. A. F. Daggett, and J. Chen
Multiple Promoter Elements Contribute to Activity of the Follicle-Stimulating Hormone Receptor (FSHR) Gene in Testicular Sertoli Cells
Mol. Endocrinol., October 1, 1998; 12(10): 1499 - 1512.
[Abstract] [Full Text]

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 EndocrinologyHome page
C. A. Flanagan, B. J. Fromme, J. S. Davidson, and R. P. Millar
A High Affinity Gonadotropin-Releasing Hormone (GnRH) Tracer, Radioiodinated at Position 6, Facilitates Analysis of Mutant GnRH Receptors
Endocrinology, October 1, 1998; 139(10): 4115 - 4119.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
R. N. Yu, M. Ito, and J. L. Jameson
The Murine Dax-1 Promoter Is Stimulated by SF-1 (Steroidogenic Factor-1) and Inhibited by COUP-TF (Chicken Ovalbumin Upstream Promoter-Transcription Factor) via a Composite Nuclear Receptor-Regulatory Element
Mol. Endocrinol., July 1, 1998; 12(7): 1010 - 1022.
[Abstract] [Full Text]

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 EndocrinologyHome page
T. R. Kumar, K. E. Graham, S. L. Asa, and M. J. Low
Simian Virus 40 T Antigen-Induced Gonadotroph Adenomas: A Model of Human Null Cell Adenomas
Endocrinology, July 1, 1998; 139(7): 3342 - 3351.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
L. M. Halvorson, M. Ito, J. L. Jameson, and W. W. Chin
Steroidogenic Factor-1 and Early Growth Response Protein 1 Act through Two Composite DNA Binding Sites to Regulate Luteinizing Hormone beta -Subunit Gene Expression
J. Biol. Chem., June 12, 1998; 273(24): 14712 - 14720.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
M. L. Brinkmeier, D. F. Gordon, J. M. Dowding, T. L. Saunders, S. K. Kendall, V. D. Sarapura, W. M. Wood, E. C. Ridgway, and S. A. Camper
Cell-Specific Expression of the Mouse Glycoprotein Hormone {alpha}-Subunit Gene Requires Multiple Interacting DNA Elements in Transgenic Mice and Cultured Cells
Mol. Endocrinol., May 1, 1998; 12(5): 622 - 633.
[Abstract] [Full Text]

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 Mol. Endocrinol.Home page
A. N. Harris and P. L. Mellon
The Basic Helix-Loop-Helix, Leucine Zipper Transcription Factor, USF (Upstream Stimulatory Factor), Is a Key Regulator of SF-1 (Steroidogenic Factor-1) Gene Expression in Pituitary Gonadotrope and Steroidogenic Cells
Mol. Endocrinol., May 1, 1998; 12(5): 714 - 726.
[Abstract] [Full Text]

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 J. Clin. Endocrinol. Metab.Home page
J. Ham, J. Webster, J. A. Bond, B. Jasani, M. D. Lewis, P. J. Hepburn, J. S. Davies, B. M. Lewis, D. W. Thomas, and M. F. Scanlon
Immortalized Human Pituitary Cells Express Glycoprotein {alpha}-Subunit and Thyrotropin {beta} (TSH{beta})
J. Clin. Endocrinol. Metab., May 1, 1998; 83(5): 1598 - 1603.
[Abstract] [Full Text]

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 EndocrinologyHome page
S. V. Drouva, B. Poulin, V. Manceau, and A. Sobel
Luteinizing Hormone-Releasing Hormone-Signal Transduction and Stathmin Phosphorylation in the Gonadotrope {alpha}T3-1 Cell Line
Endocrinology, May 1, 1998; 139(5): 2235 - 2239.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
U. B. Kaiser, E. Sabbagh, B. D. Saunders, and W. W. Chin
Identification of cis-Acting Deoxyribonucleic Acid Elements That Mediate Gonadotropin-Releasing Hormone Stimulation of the Rat Luteinizing Hormone {beta}-Subunit Gene
Endocrinology, May 1, 1998; 139(5): 2443 - 2451.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
M. A. Lawson, A. R. Buhain, J. C. Jovenal, and P. L. Mellon
Multiple Factors Interacting at the GATA Sites of the Gonadotropin-Releasing Hormone Neuron-Specific Enhancer Regulate Gene Expression
Mol. Endocrinol., March 1, 1998; 12(3): 364 - 377.
[Abstract] [Full Text]

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 Mol. Endocrinol.Home page
J. J. Tremblay, C. Lanctôt, and J. Drouin
The pan-Pituitary Activator of Transcription, Ptx1 (Pituitary Homeobox 1), Acts in Synergy with SF-1 and Pit1 and Is an Upstream Regulator of the Lim-Homeodomain Gene Lim3/Lhx3
Mol. Endocrinol., March 1, 1998; 12(3): 428 - 441.
[Abstract] [Full Text]

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 Mol. Endocrinol.Home page
M. Ito, R. N. Yu, and J. L. Jameson
Steroidogenic Factor-1 Contains a Carboxy-Terminal Transcriptional Activation Domain That Interacts with Steroid Receptor Coactivator-1
Mol. Endocrinol., February 1, 1998; 12(2): 290 - 301.
[Abstract] [Full Text]

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 Mol. Endocrinol.Home page
D. L. Duval, S. E. Nelson, and C. M. Clay
The Tripartite Basal Enhancer of the Gonadotropin-Releasing Hormone (GnRH) Receptor Gene Promoter Regulates Cell-Specific Expression Through a Novel GnRH Receptor Activating Sequence
Mol. Endocrinol., November 1, 1997; 11(12): 1814 - 1821.
[Abstract] [Full Text]

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 Am. J. Physiol. Endocrinol. Metab.Home page
M. Hezareh, W. Schlegel, and S. R. Rawlings
Stimulation of Ca2+ influx in alpha T3-1 gonadotrophs via the cAMP/PKA signaling system
Am J Physiol Endocrinol Metab, November 1, 1997; 273(5): E850 - E858.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
G. A. Cornwall and N. Hsia
ADAM7, A Member of the ADAM (A Disintegrin And Metalloprotease) Gene Family Is Specifically Expressed in the Mouse Anterior Pituitary and Epididymis
Endocrinology, October 1, 1997; 138(10): 4262 - 4272.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
L. L. Heckert, E. M. Wilson, and J. H. Nilson
Transcriptional Repression of the {alpha}-Subunit Gene by Androgen Receptor Occurs Independently of DNA Binding but Requires the DNA-Binding and Ligand-Binding Domains of the Receptor
Mol. Endocrinol., September 1, 1997; 11(10): 1497 - 1506.
[Abstract] [Full Text]

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 EndocrinologyHome page
J. M. McCue, C. C. Quirk, S. E. Nelson, R. A. Bowen, and C. M. Clay
Expression of a Murine Gonadotropin-Releasing Hormone Receptor-Luciferase Fusion Gene in Transgenic Mice Is Diminished by Immunoneutralization of Gonadotropin-Releasing Hormone
Endocrinology, August 1, 1997; 138(8): 3154 - 3160.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
N. Sanno, L. Jin, X. Qian, R. Y. Osamura, B. W. Scheithauer, K. Kovacs, and R. V. Lloyd
Gonadotropin-Releasing Hormone and Gonadotropin-Releasing Hormone Receptor Messenger Ribonucleic Acids Expression in Nontumorous and Neoplastic Pituitaries
J. Clin. Endocrinol. Metab., June 1, 1997; 82(6): 1974 - 1982.
[Abstract] [Full Text] [PDF]


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