| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on November 13, 2003
Accepted on January 28, 2004
-Subunit Gene Involves Smads and the TALE Homeodomain Proteins Pbx1 and Prep1
Department of Reproductive Medicine, University of California San Diego, La Jolla, California 92093
* To whom correspondence should be addressed. E-mail: pmellon{at}ucsd.edu.
Follicle-stimulating hormone (FSH) is critical for normal reproductive function in both males and females. Activin, a member of the Transforming Growth Factor-
(TGF) family of growth factors, is an important regulator of FSH expression, but little is known about the molecular mechanisms through which it acts. We used transient transfections into the immortalized gonadotrope cell line LT2 to identify three regions (at -973/-962, -167 and -134) of the ovine FSH -subunit gene that are required for full activin response. All three regions contain homology to consensus binding sites for Smad proteins, the intracellular mediators of TGF family signaling. Mutation of the distal site reduces activin responsiveness, while mutation of either proximal site profoundly disrupts activin regulation of the FSH gene. These sites specifically bind LT2 nuclear proteins in electromobility shift assays, and the -973/-962 site binds Smad4 protein. Interestingly, the protein complex binding to the -134 site contains Smad4 in association with the homeodomain proteins Pbx1 and Prep1. Using glutathione S-transferase assays, we demonstrate that Pbx1 and Prep1 interact with Smads 2 and 3 as well. The two proximal activin response elements are well conserved across species and Pbx1 and Prep1 proteins bind to the mouse gene in vivo. Furthermore, mutation of either proximal site abrogates activin responsiveness of a mouse FSH reporter gene as well, confirming their functional conservation. Our studies provide a basis for understanding activin regulation of FSH gene expression and identify Pbx1 and Prep1 as Smad partners and novel mediators of activin action.
This article has been cited by other articles:
 |
|
 |
|
  R. Sasson, S. H. Luu, V. G. Thackray, and P. L. Mellon Glucocorticoids Induce Human Glycoprotein Hormone {alpha}-Subunit Gene Expression in the Gonadotrope Endocrinology, July 1, 2008; 149(7): 3643 - 3655. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Lamba, V. Khivansara, A. C. D'Alessio, M. M. Santos, and D. J. Bernard Paired-Like Homeodomain Transcription Factors 1 and 2 Regulate Follicle-Stimulating Hormone {beta}-Subunit Transcription through a Conserved cis-Element Endocrinology, June 1, 2008; 149(6): 3095 - 3108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Blount, J. M. Vaughan, W. W. Vale, and L. M. Bilezikjian A Smad-binding Element in Intron 1 Participates in Activin-dependent Regulation of the Follistatin Gene J. Biol. Chem., March 14, 2008; 283(11): 7016 - 7026. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. G. Thackray and P. L. Mellon Synergistic Induction of Follicle-Stimulating Hormone {beta}-Subunit Gene Expression by Gonadal Steroid Hormone Receptors and Smad Proteins Endocrinology, March 1, 2008; 149(3): 1091 - 1102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. M. Diaz, S. Mori, E. Longobardi, G. Menendez, C. Ferrai, R. A. Keough, A. Bachi, and F. Blasi p160 Myb-Binding Protein Interacts with Prep1 and Inhibits Its Transcriptional Activity Mol. Cell. Biol., November 15, 2007; 27(22): 7981 - 7990. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Farnworth, Y. Wang, R. Escalona, P. Leembruggen, G. T. Ooi, and J. K. Findlay Transforming Growth Factor-{beta} Blocks Inhibin Binding to Different Target Cell Types in a Context-Dependent Manner through Dual Mechanisms Involving Betaglycan Endocrinology, November 1, 2007; 148(11): 5355 - 5368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Su, F. Shafiee-Kermani, A. J. Gore, J. Jia, J. C. Wu, and W. L. Miller Expression and Regulation of the {beta}-Subunit of Ovine Follicle-Stimulating Hormone Relies Heavily on a Promoter Sequence Likely to Bind Smad-Associated Proteins Endocrinology, September 1, 2007; 148(9): 4500 - 4508. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhu, A. S. Gleiberman, and M. G. Rosenfeld Molecular Physiology of Pituitary Development: Signaling and Transcriptional Networks Physiol Rev, July 1, 2007; 87(3): 933 - 963. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. L. Burger, D. J. Haisenleder, G. M. Wotton, K. W. Aylor, A. C. Dalkin, and J. C. Marshall The regulation of FSHbeta transcription by gonadal steroids: testosterone and estradiol modulation of the activin intracellular signaling pathway Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E277 - E285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Zheng, M. Jimenez-Linan, B. S. Rubin, and L. M. Halvorson Anterior Pituitary Gene Expression with Reproductive Aging in the Female Rat Biol Reprod, June 1, 2007; 76(6): 1091 - 1102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. B Lee, V. Khivansara, M. M Santos, P. Lamba, T. Yuen, S. C Sealfon, and D. J Bernard Bone morphogenetic protein 2 and activin A synergistically stimulate follicle-stimulating hormone {beta} subunit transcription J. Mol. Endocrinol., February 1, 2007; 38(2): 315 - 330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. McGillivray, V. G. Thackray, D. Coss, and P. L. Mellon Activin and Glucocorticoids Synergistically Activate Follicle-Stimulating Hormone {beta}-Subunit Gene Expression in the Immortalized L{beta}T2 Gonadotrope Cell Line Endocrinology, February 1, 2007; 148(2): 762 - 773. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Mamin and J. Philippe Activin A Decreases glucagon and arx Gene Expression in {alpha}-Cell Lines Mol. Endocrinol., January 1, 2007; 21(1): 259 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Lamba, M. M Santos, D. P Philips, and D. J Bernard Acute regulation of murine follicle-stimulating hormone {beta} subunit transcription by activin A J. Mol. Endocrinol., February 1, 2006; 36(1): 201 - 220. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Safwat, J. Ninomiya-Tsuji, A. J. Gore, and W. L. Miller Transforming Growth Factor {beta}-Activated Kinase 1 Is a Key Mediator of Ovine Follicle-Stimulating Hormone {beta}-Subunit Expression Endocrinology, November 1, 2005; 146(11): 4814 - 4824. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Baird, S. Davis, C. R. Antonescu, U. L. Harper, R. L. Walker, Y. Chen, A. A. Glatfelter, P. H. Duray, and P. S. Meltzer Gene Expression Profiling of Human Sarcomas: Insights into Sarcoma Biology Cancer Res., October 15, 2005; 65(20): 9226 - 9235. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. D. Cherrington, T. A. Farmerie, C. A. Lents, J. D. Cantlon, M. S. Roberson, and C. M. Clay Activin Responsiveness of the Murine Gonadotropin-Releasing Hormone Receptor Gene Is Mediated by a Composite Enhancer Containing Spatially Distinct Regulatory Elements Mol. Endocrinol., April 1, 2005; 19(4): 898 - 912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Gregory, C. T. Lacza, A. A. Detz, S. Xu, L. A. Petrillo, and U. B. Kaiser Synergy between Activin A and Gonadotropin-Releasing Hormone in Transcriptional Activation of the Rat Follicle-Stimulating Hormone-{beta} Gene Mol. Endocrinol., January 1, 2005; 19(1): 237 - 254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L L Burger, D J Haisenleder, A C Dalkin, and J C Marshall Regulation of gonadotropin subunit gene transcription J. Mol. Endocrinol., December 1, 2004; 33(3): 559 - 584. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Tomic, K. P. Miller, H. A. Kenny, T. K. Woodruff, P. Hoyer, and J. A. Flaws Ovarian Follicle Development Requires Smad3 Mol. Endocrinol., September 1, 2004; 18(9): 2224 - 2240. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Rave-Harel, M. L. Givens, S. B. Nelson, H. A. Duong, D. Coss, M. E. Clark, S. B. Hall, M. P. Kamps, and P. L. Mellon TALE Homeodomain Proteins Regulate Gonadotropin-releasing Hormone Gene Expression Independently and via Interactions with Oct-1 J. Biol. Chem., July 16, 2004; 279(29): 30287 - 30297. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
