Journal of Steroid Biochemistry & Molecular Biology 89–90 (2004) 461–465 Response element binding proteins and intracellular vitamin D binding proteins: novel regulators of vitamin D trafficking, action and metabolism  John S. Adams a,∗ , Hong Chen a , Rene Chun a , Mercedes A. Gacad a , Carlos Encinas a , Songyang Ren a , Lisa Nguyen a , Shaoxing Wu a , Martin Hewison a,b , Julia Barsony c a The Burns and Allen Research Institute, Cedars-Sinai Medical Center, UCLA School of Medicine, B131, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA, USA b Department of Medical Sciences, University of Birmingham, Birmingham, UK c Laboratory of Cell Biochemistry and Biology, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA Abstract Using vitamin D-resistant New World primates as model of natural diversity for sterol/steroid action and metabolism, two families of novel intracellular vitamin D regulatory proteins have been discovered and their human homologs elucidated. The first family of proteins, heterogeneous nuclear ribonucleoproteins (hnRNPs), initially considered to function only as pre-mRNA-interacting proteins, have been demonstrated to be potent cis-acting, trans-dominant regulators of vitamin D hormone-driven gene transactivation. The second group of proteins bind 25-hydroxylated vitamin D metabolites. Their overexpression increases vitamin D receptor (VDR)-directed target gene expression. We found that these intracellular vitamin D binding proteins (IDBPs) are homologous to proteins in the heat shock protein-70 family. Our ongoing studies indicate directly or indirectly through a series of protein interactions that the IDBPs interact with hydroxylated vitamin D metabolites and facilitate their intracellular targeting. © 2004 Elsevier Ltd. All rights reserved. Keywords: Vitamin D; Binding proteins; Receptors; Transcription; Resistance; Metabolism; Traffic; Heat shock proteins; Heterogeneous nuclear ribonucleoproteins 1. In the beginning In the Eocene period, some 50–100 million years ago, the great southern hemispheric land mass, Pangea, broke apart with the Americas and Madagascar moving away from Africa. This continental separation occurred early in the process of primate evolution, trapping primordial primates in South America, Africa, and Madagascar. Because they lacked aquatic mobility, the three major primate infraorders, platyrrhines or New World primates, the catarrhines or Old World primates and lemurs (i.e. prosimians), respectively, evolved independently of one another on these three sepa- rate land masses [1]. Compared to Old World primates, in- cluding Homo sapiens which exhibit a worldwide distribu- tion today, New World primates are confined to South and  Presented at the 12th Workshop on Vitamin D (Maastricht, The Nether- lands, 6–10 July 2003). ∗ Corresponding author. Tel.: +1-310-423-8970; fax: +1-310-423-4550. Central America roughly 20 ◦ latitude north and south of the equator. They are generally smaller in stature which is well suited to their lifestyle as herbivorous sunbathers, re- siding in the canopy of the periequatorial rain forests of the Americas. 2. Lessons learned from an outbreak of rickets in the New World primate colonies of the Los Angeles Zoo In the mid-1980s, the authors were asked to investigate the cause and provide a treatment for a rachitic bone disease that was rampant among pre-adolescent New World primate residents of the Los Angeles Zoo. The disorder was most se- vere among monkeys of the Emperor tamarin species. When investigated radiographically, affected monkeys displayed classical rickets. Compared to unaffected age-matched sib- lings, these animals had smaller skeletons and metaphyseal cupping and fraying characteristic of rickets. 0960-0760/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2004.03.016