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Adrenocortical Tumorigenesis in Transgenic Mice Expressing the Inhibin -Subunit Promoter/Simian Virus 40 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, Missouri 63110; and Institute of Reproductive and Developmental Biology (I.H.), Imperial College London, Faculty of Medicine, London W12 0NN, United Kingdom

Address all correspondence and requests for reprints to: Ilpo Huhtaniemi, M.D., Ph.D., Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom. 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 months and preceded the appearance of discernible adrenal tumors at about 6 months. 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 nonsteroidogenic human embryonic kidney 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/human chorionic gonadotropin stimulation of LHR promoter activity; mutations or deletion of the consensus GATA-4 binding site of the LHR promoter abolished this transactivation. EMSAs 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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