| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLES |
I-Mediated Activation of Phosphotyrosine Phosphatase1
Department of Gynecology and Obstetrics, Georg August University, D-37070 Gottingen, Germany
Address all correspondence and requests for reprints to: Prof. Dr. Günter Emons, Department of Gynecology and Obstetrics, Robert Koch Street 40, D-37075 Gottingen, Germany. E-mail: emons{at}med.uni-goettingen.de
The signaling pathway through which LHRH acts in endometrial and ovarian cancers is distinct from that in the anterior pituitary. The LHRH receptor interacts with the mitogenic signal transduction of growth factor receptors, resulting in down-regulation of expression of c-fos and proliferation. Only limited data are available on the cross-talk between LHRH receptor signaling and inhibition of mitogenic signal transduction.
The present experiments were performed to analyze in endometrial and ovarian cancer cells: 1) whether mutations or splice variants of the LHRH receptor are responsible for differences in LHRH signaling, 2) the coupling of G protein subtypes to LHRH receptor, 3) the phosphotyrosine phosphatase (PTP) activation counteracting growth factor receptor tyrosine kinase activity. For these studies, the well characterized human Ishikawa and Hec-1A endometrial cancer cell lines and human EFO-21 and EFO-27 ovarian cancer cell lines were used, which express LHRH and its receptor.
1) Sequencing of the complementary DNA of the LHRH receptor from
position 31 to position 1204, covering the complete coding region
(position 56 to position 1042) showed that there are neither mutations
nor splice variants of the LHRH receptor transcript in Ishikawa and
Hec-1A endometrial cancer cells or in EFO-21 and EFO-27 ovarian cancer
cells. 2) All analyzed cell lines except for the ovarian cancer cell
line EFO-27 expressed both G proteins, 
i and
q, as shown by RT-PCR and Western blotting. In the
EFO-27 cell line only G protein i, not G protein
q, expression was found. Cross-linking experiments using
disuccinimidyl suberate revealed that in the cell lines expressing G
protein i and G protein q, both G
proteins coupled to the LHRH receptor. Inhibition of epidermal growth
factor (EGF)-induced c-fos expression by LHRH, however,
was mediated through pertussis toxin (PTX)-sensitive G protein
i. Moreover, LHRH substantially antagonized the
PTX-catalyzed ADP-ribosylation of G protein i. 3) Using
a phosphotyrosine phosphatase assay based on molybdate-malachite green,
treatment of quiescent EFO-21 and EFO-27 ovarian cancer cells and
quiescent Ishikawa and Hec-1A endometrial cancer cells with 100
nM of the LHRH agonist triptorelin resulted in a 4-fold
increase in PTP activity (P < 0.001). This effect
was completely blocked by simultaneous treatment with PTX, supporting
the concept of mediation through G protein i. As shown
by quantitative Western blotting, EGF-induced tyrosine
autophosphorylation of EGF receptors was reduced 45–63% after LHRH
(100 nM) treatment (P < 0.001). This
effect was completely blocked using the PTP inhibitor vanadate
(P < 0.001).
These results demonstrate that mutations or splice variants of the LHRH
receptor in human endometrial and ovarian cancer cells are not
responsible for the different signal transduction compared with that in
pituitary gonadotrophs. We provide evidence that the tumor LHRH
receptor couples to multiple G proteins, but the antiproliferative
signal transduction is mediated through the PTX-sensitive G protein
i. The tumor LHRH receptor activates a PTP counteracting
EGF-induced tyrosine autophosphorylation of EGF receptor, resulting in
down-regulation of mitogenic signal transduction and cell
proliferation.
This article has been cited by other articles:
 |
|
 |
|
  M. Montagnani Marelli, R. M. Moretti, S. Mai, J. Januszkiewicz-Caulier, M. Motta, and P. Limonta Type I Gonadotropin-Releasing Hormone Receptor Mediates the Antiproliferative Effects of GnRH-II on Prostate Cancer Cells J. Clin. Endocrinol. Metab., May 1, 2009; 94(5): 1761 - 1767. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-M. Wu, H.-S. Wang, H.-Y. Huang, Y.-K. Soong, C. D MacCalman, and P. C K Leung GnRH signaling in intrauterine tissues Reproduction, May 1, 2009; 137(5): 769 - 777. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. White, M. Coetsee, K. Morgan, C. A. Flanagan, R. P. Millar, and Z.-L. Lu A Crucial Role for G{alpha}q/11, But Not G{alpha}i/o or G{alpha}s, in Gonadotropin-Releasing Hormone Receptor-Mediated Cell Growth Inhibition Mol. Endocrinol., November 1, 2008; 22(11): 2520 - 2530. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Morgan, A. J. Stewart, N. Miller, P. Mullen, M. Muir, M. Dodds, F. Medda, D. Harrison, S. Langdon, and R. P. Millar Gonadotropin-Releasing Hormone Receptor Levels and Cell Context Affect Tumor Cell Responses to Agonist In vitro and In vivo Cancer Res., August 1, 2008; 68(15): 6331 - 6340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Lopez de Maturana, A. J. Pawson, Z.-L. Lu, L. Davidson, S. Maudsley, K. Morgan, S. P. Langdon, and R. P. Millar Gonadotropin-Releasing Hormone Analog Structural Determinants of Selectivity for Inhibition of Cell Growth: Support for the Concept of Ligand-Induced Selective Signaling Mol. Endocrinol., July 1, 2008; 22(7): 1711 - 1722. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. P. Ford, K. V. Wong, V. B. Lu, E. Posse de Chaves, and P. A. Smith Differential Neurotrophic Regulation of Sodium and Calcium Channels in an Adult Sympathetic Neuron J Neurophysiol, March 1, 2008; 99(3): 1319 - 1332. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Walters, I. N. Wegorzewska, Y.-P. Chin, M. G. Parikh, and T. J. Wu Luteinizing Hormone-Releasing Hormone I (LHRH-I) and Its Metabolite in Peripheral Tissues Experimental Biology and Medicine, February 1, 2008; 233(2): 123 - 130. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Stewart, R. Sellar, D. J. Wilson, R. P. Millar, and Z.-L. Lu Identification of a Novel Ligand Binding Residue Arg38(1.35) in the Human Gonadotropin-Releasing Hormone Receptor Mol. Pharmacol., January 1, 2008; 73(1): 75 - 81. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Gardner, S. Maudsley, R. P. Millar, and A. J. Pawson Nuclear Stabilization of {beta}-Catenin and Inactivation of Glycogen Synthase Kinase-3{beta} by Gonadotropin-Releasing Hormone: Targeting Wnt Signaling in the Pituitary Gonadotrope Mol. Endocrinol., December 1, 2007; 21(12): 3028 - 3038. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Chiellini, S. Frascarelli, S. Ghelardoni, V. Carnicelli, S. C. Tobias, A. DeBarber, S. Brogioni, S. Ronca-Testoni, E. Cerbai, D. K. Grandy, et al. Cardiac effects of 3-iodothyronamine: a new aminergic system modulating cardiac function FASEB J, May 1, 2007; 21(7): 1597 - 1608. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. C.K. Leung and J.-H. Choi Endocrine signaling in ovarian surface epithelium and cancer Hum. Reprod. Update, March 1, 2007; 13(2): 143 - 162. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Baldwin, I. N. Wegorzewska, M. Flora, and T. J. Wu Regulation of Type II Luteinizing Hormone-Releasing Hormone (LHRH-II) Gene Expression by the Processed Peptide of LHRH-I, LHRH-(1-5) in Endometrial Cells Experimental Biology and Medicine, January 1, 2007; 232(1): 146 - 155. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R Gunthert, C. Grundker, A. Olota, J. Lasche, N. Eicke, and G. Emons Analogs of GnRH-I and GnRH-II inhibit epidermal growth factor-induced signal transduction and resensitize resistant human breast cancer cells to 4OH-tamoxifen Eur. J. Endocrinol., October 1, 2005; 153(4): 613 - 625. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Levens, X. Luo, L. Ding, R. S. Williams, and N. Chegini Fibromodulin is expressed in leiomyoma and myometrium and regulated by gonadotropin-releasing hormone analogue therapy and TGF-{beta} through Smad and MAPK-mediated signalling Mol. Hum. Reprod., July 1, 2005; 11(7): 489 - 494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. K. Cheng and P. C. K. Leung Molecular Biology of Gonadotropin-Releasing Hormone (GnRH)-I, GnRH-II, and Their Receptors in Humans Endocr. Rev., April 1, 2005; 26(2): 283 - 306. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Chen, S. Yoshida, N. Ohara, H. Matsuo, M. Morizane, and T. Maruo Gonadotropin-Releasing Hormone Antagonist Cetrorelix Down-Regulates Proliferating Cell Nuclear Antigen and Epidermal Growth Factor Expression and Up-Regulates Apoptosis in Association with Enhanced Poly(Adenosine 5'-Diphosphate-Ribose) Polymerase Expression in Cultured Human Leiomyoma Cells J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 884 - 892. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G S Harrison, M E Wierman, T M Nett, and L M Glode Gonadotropin-releasing hormone and its receptor in normal and malignant cells Endocr. Relat. Cancer, December 1, 2004; 11(4): 725 - 748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Luo, L. Ding, and N. Chegini Gonadotropin-releasing hormone and TGF-{beta} activate MAP kinase and differentially regulate fibronectin expression in endometrial epithelial and stromal cells Am J Physiol Endocrinol Metab, November 1, 2004; 287(5): E991 - E1001. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Maudsley, L. Davidson, A. J. Pawson, R. Chan, R. L. de Maturana, and R. P. Millar Gonadotropin-Releasing Hormone (GnRH) Antagonists Promote Proapoptotic Signaling in Peripheral Reproductive Tumor Cells by Activating a G{alpha}i-Coupling State of the Type I GnRH Receptor Cancer Res., October 15, 2004; 64(20): 7533 - 7544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Millar, Z.-L. Lu, A. J. Pawson, C. A. Flanagan, K. Morgan, and S. R. Maudsley Gonadotropin-Releasing Hormone Receptors Endocr. Rev., April 1, 2004; 25(2): 235 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. G. Romanelli, T. Barni, M. Maggi, M. Luconi, P. Failli, A. Pezzatini, E. Pelo, F. Torricelli, C. Crescioli, P. Ferruzzi, et al. Expression and Function of Gonadotropin-releasing Hormone (GnRH) Receptor in Human Olfactory GnRH-secreting Neurons: AN AUTOCRINE GnRH LOOP UNDERLIES NEURONAL MIGRATION J. Biol. Chem., January 2, 2004; 279(1): 117 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Bajo, A. V. Schally, G. Halmos, and A. Nagy Targeted Doxorubicin-containing Luteinizing Hormone-releasing Hormone Analogue AN-152 Inhibits the Growth of Doxorubicin-resistant MX-1 Human Breast Cancers Clin. Cancer Res., September 1, 2003; 9(10): 3742 - 3748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Chamson-Reig, E. M. Sorianello, P. N. Catalano, M. O. Fernandez, O. P. Pignataro, C. Libertun, and V. A. R. Lux-Lantos Gonadotropin-Releasing Hormone Signaling Pathways in an Experimental Ovarian Tumor Endocrinology, July 1, 2003; 144(7): 2957 - 2966. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Chegini, J. Verala, X. Luo, J. Xu, and R. S. Williams Gene Expression Profile of Leiomyoma and Myometrium and the Effect of Gonadotropin Releasing Hormone Analogue Therapy Reproductive Sciences, April 1, 2003; 10(3): 161 - 171. [Abstract] [PDF]
|
|
|
|
|
|
N. Chegini, C. Ma, X.M. Tang, and R.S. Williams Effects of GnRH analogues, `add-back' steroid therapy, antiestrogen and antiprogestins on leiomyoma and myometrial smooth muscle cell growth and transforming growth factor-{beta} expression Mol. Hum. Reprod., December 1, 2002; 8(12): 1071 - 1078. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Morales, C. Pasten, and E. Pizarro Inhibition of In Vivo and In Vitro Fertilization in Rodents by Gonadotropin-Releasing Hormone Antagonists Biol Reprod, October 1, 2002; 67(4): 1360 - 1365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Tang, T. Yano, Y. Osuga, H. Matsumi, N. Yano, J. Xu, O. Wada, K. Koga, K. Kugu, O. Tsutsumi, et al. Cellular Mechanisms of Growth Inhibition of Human Epithelial Ovarian Cancer Cell Line by LH-Releasing Hormone Antagonist Cetrorelix J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3721 - 3727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Everest, J. N. Hislop, T. Harding, J. B. Uney, A. Flynn, R. P. Millar, and C. A. McArdle Signaling and Antiproliferative Effects Mediated by GnRH Receptors After Expression in Breast Cancer Cells Using Recombinant Adenovirus Endocrinology, November 1, 2001; 142(11): 4663 - 4672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Levens, X. Luo, L. Ding, R. S. Williams, and N. Chegini Fibromodulin is expressed in leiomyoma and myometrium and regulated by gonadotropin-releasing hormone analogue therapy and TGF-{beta} through Smad and MAPK-mediated signalling Mol. Hum. Reprod., July 1, 2005; 11(7): 489 - 494. [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 |
