Julianne J. Sando, PhD
Protein Kinase C in control of gene expression, growth and differentiation
The major focus of the Sando lab has been on structure and activation of Protein kinase C (PKC) isozymes. This project is relevant to cancer because PKC is the major receptor for tumor-promoting phorbol esters and because different PKC isozymes are implicated in different cellular responses relevant to cancer including growth, apoptosis, invasiveness, and angiogenesis. PKCs are activated upon binding to cellular membranes and they have characterized some of the essential properties of the activating lipid domains. In work funded by an RO1 with Drs. A. Solodukhin and R. Kretsinger as coPIs, they have generated 2D crystals of PKCs bound to lipid monolayers and analyzed these via electron microscopy. A major paper describing 3D reconstruction of PKCd from analysis of tilted 2D crystals is in preparation now. A second newer project addresses regulation of ghrelin structure and function by PKC. Ghrelin is a newly discovered basic peptide hormone produced by the stomach, heart, lymphocytes and other tissues. It is of interest in the context of cancer for several reasons: It is a potent appetite stimulant, thus ghrelin or mimetics may be useful in cancer-associated cachexia. Some tumors produce elevated concentrations of ghrelin. In addition, ghrelin is anti-inflammatory and may be involved in some pain pathways. Ghrelin is unusual in requiring acylation for binding to its G-protein-coupled receptor; although desacylghrelin has some shared and some unique effects. The ghrelin receptor undergoes internalization and they have hypothesized that ghrelin may act inside cells via binding to acidic lipid-rich domains where it may be subject to regulation by PKC. A new RO1 with Drs. Bruce Gaylinn and Manoj Patel as coPIs and Drs. Andra Stevenson, Avril Somlyo and Dave Cafiso as collaborators/consultants is just being submitted. They have found that ghrelin is phosphorylated by PKC, that ghrelin but not phosphghrelin binds to acidic lipid vesicles, and that ghrelin inhibits activity of a neuronal Na channel implicated in pain pathways. They are initiating analysis of the effects of phosphorylation on ghrelin structure via circular dichroism.