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Submitted on August 14, 2002
Accepted on July 6, 2004
-subunit promoter/SV40 virus T-antigen transgene: Relationship between ectopic expression of luteinizing hormone receptor and transcription factor GATA-4
Department of Physiology (N.A.R., A.R.-M., J.L., S.V. J.K., I.H.), University of Turku, 20520 Turku, Finland; Program for Developmental and Reproductive Biology, Biomedicum Helsinki and Children's Hospital (S.K., M.H.), University of Helsinki, 00029 Helsinki, Finland; Departments of Pediatrics (D.B.W, M.H.), and Pharmacology (D.B.W), Washington University, St. Louis, MO 63110, USA, Institute of Reproductive and Developmental Biology (I.H.), Imperial College London, Faculty of Medicine, London W12 0NN, UK
* To whom correspondence should be addressed. E-mail: ilpo.huhtaniemi{at}imperial.ac.uk.
We have analyzed the ontogeny and putative mechanisms of transregulation of LH receptor (LHR) and transcription factor GATA-4, coexpressed during the adrenocortical tumorigenesis of prepubertally gonadectomized transgenic (TG) mice expressing the inhibin 
-subunit promoter/Simian Virus 40 T-antigen (inh/Tag) transgene. The onset of adrenal LHR mRNA and protein expression coincided with that of GATA-4 at the age of 4 mo and preceded the appearance of discernible adrenal tumors at about 6 mo. In situ hybridization and double-immunohistochemistry demonstrated colocalization of the LHR and GATA-4 messages and proteins in the adrenal cortex. A GATA-4 expression plasmid cotransfected with a murine LHR promoter-driven luciferase reporter plasmid, containing a consensus GATA-binding site, induced a dose-dependent significant transactivation of the LHR promoter in non-steroidogenic HEK 293, steroidogenic murine mLTC-1 Leydig cells and in murine adrenal Y-1 cells. The C1 cells derived from an Inh/Tag adrenal tumor did not show this response, apparently due to their high endogenous GATA-4 expression. However, an additional link between GATA-4 and LHR in C1 cells was provided upon the LH/hCG stimulation of LHR promoter activity; mutations or deletion of the consensus GATA-4 binding site of the LHR promoter abolished this transactivation. Electrophoretic mobility shift assays further proved GATA-4 binding to the putative consensus GATA recognition site. Our results demonstrate direct interrelationship between LHR and GATA-4 expression during adrenocortical tumorigenesis of the inh/Tag mice. There is apparently a positive and reciprocal feed-forward amplification link between LHR and GATA-4 expression. This mechanism gradually and in synergy with Tag expression leads to formation of the LH-dependent adrenocortical tumors.
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