Linda Nicholson, Department of Molecular Biology and Genetics

The main thrust of the research in the Nicholson laboratory is to combine structure, dynamics, and thermodynamic measurements to study the fundamental principles governing ligand binding to the SH3 and SH2 domains of Src, and to test whether functional fragments of the Src regulatory apparatus accurately mimic function in the intact protein. This represents a major collaborative effort with the Shalloway group, another laboratory participating in this proposal. The issues being examined are at the heart of two current frontiers in science: rational drug design, and elucidation of the molecular basis of intracellular signal transduction.

Alexander Nikitin, College of Veterinary Medicine
Cancer Pathology and generation of transgenic models of cancer.

Noa Noy, Dept of Nutritional Sciences

Retinoic acids play critical roles in differentiation and proliferation of cells in both embryonic and adult tissues, and they are currently used as therapeutic agents in a variety of clinical settings ranging from dermatological disorders to cancer. The pleiotropic effects of retinoic acids on physiology originate from their ability to regulate transcription of multiple target genes. These activities are mediated by two classes of ligand-activated transcription factors: the retinoic acid- and the retinoid X-receptors (designated RARs and RXRs, respectively).

RXRs are of particular interest because the activities of a number of other nuclear receptors, such as RAR, the thyroid hormone-, vitamin D-, and the peroxisome proliferator-activated-receptors (abbreviated TR, VDR, and PPAR), critically depend on their ability to heterodimerize with RXR. Hence, RXR serves as a ‘master regulator’ of multiple signaling pathways emanating from a variety of lipophilic hormones and nutrients and converging at the genome.

Recent work from the Noy laboratory has revealed that RXR is also unique in that it forms tetramers with a high affinity and in a cooperative manner. In addition, the oligomeric state of RXR was found to be tightly regulated by its cognate ligand, suggesting that ligand-induced dissociation of tetramers is the first step in the activation of RXR.

In addition to retinoid receptors, two other intracellular proteins, cellular retinoic acid-binding protein I and II (CRABP-I and CRABP-II), are believed to be involved in regulating retinoic acid signaling. The Noy laboratory has found that CRABP-II, but not CRABP-I, enhances the activity of retinoid receptors by facilitating the delivery of retinoic acid to these receptors, and that this process is mediated by direct protein-protein interactions between CRABP-II and RAR.

The studies being performed in the Noy laboratory are designed to further delineate the molecular mechanisms by which the activities of retinoid receptors are regulated. The long term objective of this laboratory is to clarify how the interactions of retinoid receptors with ligands, DNA, and other proteins govern their biological activities. Structure-function studies in collaboration with the Ealick laboratory (see B3b., below) are being directed toward determining how the formation of various oligomers of RXR (homotetramers, homodimers, and heterodimers with partner receptors such as RAR and the vitamin D receptor) is controlled by a complex interplay between cognate ligands for RXR and its partner receptors.