Hormone response element binding proteins: novel regulators of vitamin D and estrogen signaling

Abstract

Insights from vitamin D-resistant New World primates and their human homologues as models of natural and pathological insensitivity to sterol/steroid action have uncovered a family of novel intracellular vitamin D and estrogen regulatory proteins involved in hormone action. The proteins, known as "vitamin D or estrogen response element-binding proteins", behave as potent cis-acting, transdominant regulators to inhibit steroid receptor binding to DNA response elements and is responsible for vitamin D and estrogen resistances. This set of interactors belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family of previously known pre-mRNA-interacting proteins. This review provides new insights into the mechanism by which these novel regulators of signaling and metabolism can act to regulate responses to vitamin D and estrogen. In addition the review also describes other molecules that are known to influence nuclear receptor signaling through interaction with hormone response elements.

Figure 1. Steroid receptor induction of gene transcription: a multi-step control model of VDR activity at the genomic and post-translational levels

1α,25-dihydroxyvitamin D₃ (vitamin D₃) is a hormone that plays a crucial role in the regulation/metabolism of calcium and phosphorus in the small intestine, kidney and bone. In addition it is also involved in immune function, tumor suppression, growth regulation and parathyroid hormone secretion. Serving an endocrine role, free (i.e. unbound) steroids can enter the cell cytoplasm and interact with their receptor. For certain cell types, vitamin D₃ can be self synthesized in the cytoplasm. In this process heat shock proteins are dissociated, and the activated receptor-ligand complex is translocated into the nucleus. VDR, the vitamin D₃ receptor, exists as a heterodimer with RXR. Vitamin D₃-bound VDR-RXR, along with other co-activator and co-repressor proteins, mediates the transcriptional regulation of a number of genes in the nucleus. Importantly, VDRE-BPs also mediate transcription of VDR-responsive genes involved in hormone, bone and growth regulation. Hence any disruption to the vitamin or its receptor would have consequences in a number of the key physiological processes. Furthermore at the post-receptor level, defective co-activator or excessive co-repressor activity could lead to nuclear hormone resistance affecting multiple nuclear hormonal receptor systems. Data were analyzed and validated (e.g. citations) through the use of Ingenuity Pathways Analysis (Ingenuity® Systems, www.ingenuity.com)