Targeted oncogenesis reveals a distinct tissue-specific utilization of alternative promoters of the human mineralocorticoid receptor gene in transgenic mice

The human mineralocorticoid receptor (hMR) is a nuclear receptor mediating aldosterone action, whose expression is driven by two alternative promoters , P1 and P2, flanking the two first 5'-untranslated exons. In vivo characte rization of hMR regulatory regions was performed by targeted oncogenesis in mice using PI or Pa directing expression of the large T antigen of SV40 (T Ag). While transgenic P1.TAg founders rapidly developed lethal hibernomas f rom brown fat, cerebral primitive neuroectodermal tumors and facial leiomyo sarcomas occurred in P2.TAg mice. Quantitative analyses of mouse MR (mMR) a nd transgene expression indicate that P1 promoter was transcriptionally act ive in all MR-expressing tissues, directing strong TAg expression in testis and salivary glands, moderate in lung brain, uterus, liver, and heart but, unlike mMR, rather low in colon and kidney. Importantly, the renal transge ne expression colocalized with mMR in the distal nephron. In contrast, P2 p romoter was approximately 10 times less potent than P1, with no activity in the brain and colon. Several immortalized cell lines were established from both neoplastic and normal tissues of transgenic mice. These cells exhibit ed differentiated characteristics and maintained MR expression, thus provid ing useful models for further studies exploring the widespread expression a nd functions of MR. Our results demonstrate that hMR gene expression in viv o is controlled by complex regulatory mechanisms involving distinct tissue- specific utilization of alternative promoters.