Department of Cellular and Molecular Medicine
Lipophilic hormones and nutrients often control biological processes by regulating transcription of specific target genes. Our overall goals are to understand the mechanisms that underlie the transcriptional activities of lipid-soluble compounds, to map the gene networks that mediate their actions, and to link these molecular foundations to the functions of these compounds in health and disease. One of our programs focuses on the vitamin A metabolite retinoic acid (RA), which activates transcription factors of the nuclear receptor family. We discovered that, in addition to activating the classical RA receptors (RARs), RA also serves as a ligand to the nuclear receptor PPARδ, and we delineated the mechanism by which the partitioning of the hormone between the two pathways is regulated. This dual transcriptional activity of RA has far-reaching implications for biological processes ranging from regulation of energy homeostasis and insulin responses to control of neuronal cell function and cancer cell growth. Another program is based on our discovery that the parental vitamin A molecule (retinol), in complex with its blood carrier protein (RBP), is a transcriptional regulator in its own right. We found that a membrane protein termed STRA6 is both a retinol transporter and a surface signaling receptor which, upon activation by retinol-RBP, triggers JAK/STAT signaling that culminates in induction of specific genes. The STRA6 pathway thus plays key roles in multiple cells and organs where it controls biological activities including insulin responses and cell growth. A third program originated from our recent discovery that, in addition to its involvement in regulation of gene transcription, cellular RA binding protein 2 also controls mRNA stability. We are currently exploring the involvement of RA and its binding proteins in RNA biology.
In other words ...
My laboratory has had a long-standing interest in understanding the biological activities of small lipid-like nutrients and hormones, and in the involvement of such compounds in normal and pathological processes. We discovered that the active metabolite of vitamin A - retinoic acid - can regulate gene expression by two distinct pathways. We also discovered that the parental vitamin A molecule in complex with its serum carrier protein functions as a signaling molecule which controls cell function independently of the role of the vitamin in giving rise to active metabolites. These discoveries opened new windows on vitamin A biology, and they point at novel strategies in therapy of pathologies including obesity, insulin resistance, and cancer.