HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 50, 52500-52516, December 10, 2004

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 279/50/52500    most recent M404571200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rose, A. Articles by Dupont, J. Search for Related Content PubMed PubMed Citation Articles by Rose, A. Articles by Dupont, J. Social Bookmarking                      What's this?

The Luteinizing Hormone-releasing Hormone Inhibits the Anti-apoptotic Activity of Insulin-like Growth Factor-1 in Pituitary T3 Cells by Protein Kinase C-mediated Negative Regulation of Akt^*

Annabel Rose, Pascal Froment, Valérie Perrot, Michael J. Quon¶, Derek LeRoith||, and Joëlle Dupont**

From the Unité de Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique, 37380 Nouzilly, UMR INSERM U-449/INRA 1235, RTH Laënnec Medical School, University of Lyon I, 69372 Lyon, France, ^¶Diabetes Unit, Laboratory of Clinical Investigation, NCCAM, and ^||Section on Molecular and Cellular Physiology, Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892

The luteinizing hormone-releasing hormone (LHRH) receptor is a G protein-coupled receptor involved in the synthesis and release of pituitary gonadotropins and in the proliferation and apoptosis of pituitary cells. Insulin-like growth factor-1 receptor (IGF-1R) is a tyrosine kinase receptor that has a mitogenic effect on pituitary cells. In this study, we used the T3 gonadotrope cell line as a model to characterize the IGF-1R signaling pathways and to investigate whether this receptor interacts with the LHRH cascade. We found that IGF-1 activated the IGF-1R, insulin receptor substrate (IRS)-1, phosphatidylinositol 3-kinase, and Akt in a time-dependent manner in T3 cells. The MAPK (ERK1/2, p38, and JNK) pathways were only weakly activated by IGF-1. In contrast, LHRH strongly stimulated the MAPK pathways but had no effect on Akt activation. Cotreatment with IGF-1 and LHRH had various effects on these signaling pathways. 1) It strongly increased IGF-1-induced tyrosine phosphorylation of IRS-1 and IRS-1-associated phosphatidylinositol 3-kinase through activation of the epidermal growth factor receptor. 2) It had an additive effect on ERK1/2 activation without modifying the phosphorylation of p38 and JNK1/2. 3) It strongly reduced IGF-1 activation of Akt. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and cell cycle analysis revealed that, in addition to having an additive effect on ERK1/2 activation, cotreatment with IGF-1 and LHRH also had an additive effect on cell proliferation. The LHRH-induced inhibition of Akt stimulated by IGF-1 was completely blocked by Safingol, a protein kinase C (PKC) -specific inhibitor, and by a dominant negative form of PKC. Finally, we showed that the inhibitory effect of LHRH on IGF-1-induced PKC-mediated Akt activation was associated with a marked reduction in Bad phosphorylation and a substantial decrease in the ability of IGF-1 to rescue T3 cells from apoptosis induced by serum starvation. Our results demonstrate for the first time that several interactions take place between IGF-1 and LHRH receptors in gonadotrope cells.

Received for publication, April 26, 2004 , and in revised form, September 23, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Fig. 1.

^** To whom correspondence should be addressed: Unité de Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique, Nouzilly 37380, France. Tel.: 33-2-47-42-79-64; Fax: 33-2-47-42-77-43; E-mail: jdupont{at}tours.inra.fr.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M.-H. T. Do, S. J. Santos, and M. A. Lawson GNRH Induces the Unfolded Protein Response in the L{beta}T2 Pituitary Gonadotrope Cell Line Mol. Endocrinol., January 1, 2009; 23(1): 100 - 112. [Abstract] [Full Text] [PDF]

				J. T. Ross, I. C. McMillen, F. Lok, A. G. Thiel, J. A. Owens, and C. L. Coulter Intrafetal Insulin-Like Growth Factor-I Infusion Stimulates Adrenal Growth But Not Steroidogenesis in the Sheep Fetus during Late Gestation Endocrinology, November 1, 2007; 148(11): 5424 - 5432. [Abstract] [Full Text] [PDF]