Endocrine Abstracts

We recently generated a transgenic reporter mouse, named ERE-Luc, to study the transcriptional activity of estrogen receptors (ERs) in patho-physiological states and showed that in this model system the synthesis of luciferase is strictly associated with an augmented transcriptional activity of both ERα and ERβ receptors but is independent from the activity of receptors related to ERs. Studies on ER activity in sexually mature, adult female mice showed that in cycling females the state of ER activity is proportional to the levels of circulating estradiol only in reproductive organs and liver. In non-reproductive organs factors other than estradiol appear to be responsible for ER transcriptional activation. Using antagonists of IGF-1 receptors and IGF-1 liver conditional k.o. mice we demonstrate that IGF-1 regulates ER-dependent transcription in several ER positive tissues. This is in accordance with previous reports showing that the intracellular signalling cascade induced by IGF-1 may induce ER transcription in culture cells. These findings are of particular interest considering the major role played by IGF-1 in the selection of metabolic paths determining proliferation or increased life span in nematodes and insects. We hypothesize that a functional link between ER and IGF receptors is rooted in the phylogenesis and is maintained in more evolved organisms because providing physiological advantages which will be discussed.

The consequences of long term treatments with natural and synthetic ER ligands were studied by daily measurements of bioluminescence emission in treated female ERE-Luc mice. It is shown that in most target organs ER trascriptional activity fluctuates in time and synthetic ligands reinstate the oscillatory ER transcriptional activity of naturally cycling mice only when administered at therapeutic doses. These findings point to the physiological relevance of oscillatory ER activity and to its requirement to elicit the tissue-specific protective effects linked to estrogen action.