Endocrine Abstracts

For the last two decades this laboratory has been investigating the states of vitamin D and gonadal steroid hormone resistance in New World primate (platyrrhine) species. Hormone resistance results from the constitutive over-expression of proteins in the heterogeneous nuclear ribonucleoprotein (hnRNP) A and C families. These proteins, originally considered to bind and 'stabilize' single strand pre-mRNAs destined for translation, also bind DNA, regulating both the transcription and splicing of nascent transcripts. It is the ability of these hnRNPS, when over-produced, to accumulate in the nuclear compartment of the cell and compete in trans with vitamin D receptor (VDR), retinoid X receptor (RXR) and estrogen receptoralpha (ER) dimer pairs for interaction with cognate response element cis sites that results in inhibition of vitamin D and estrogen-directed transactivation. Most recently, we have 1] defined a human with VDR-RXR-normal, ligand-reversible vitamin D resistance due to over expression of an hnRNP in the A family and 2] created a model of breast-specific estrogen resistance by tissue-targeted over-expression of the hnRNPC-related estrogen response element binding protein (ERE-BP) in the mouse. A series of such breast-targeted transgenics displaying low, intermediate and high levels of the transgene expression under control of the whey acidic protein promoter demonstrate a of spectrum of minimally-to-greatly retarded ERalpha-directed breast development. We hypothesize that the eventual ability to modify, up and down, expression of these dominant-negative-acting hnRNPs in the human host will provide a means of antagonizing and amplifying the genomic actions of steroid hormones in their respective target tissues.