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Stephen Prescott

Professor of Internal Medicine and of Oncological Sciences

Degrees

Research

References

stephen.prescott@hci.utah.edu

Stephen Prescott's Lab Page

Research

In the last 20 years, lipids have come to be appreciated as critical signaling molecules, in addition to their well understood role as structural components of the cell.  The projects in my lab address the issues of how cells translate extracellular messages into internal signals through lipid signaling molecules. We are particularly interested in enzymes that generate signals for growth and differentiation, as these enzymes play a role in many diseases, including cancer. A related area of interest is how the inflammation process is regulated.

Prostaglandins are lipid messengers that have been implicated as important signals in many normal cellular events as well as disease mechanisms. To study the synthesis of prostaglandins from the essential fatty acid, arachidonic acid, we isolated cDNAs that encode the synthetic enzymes and determined the key regulatory steps. For example, the central enzyme that converts arachidonic acid to prostaglandins, cyclooxygenase-2 (COX-2), is normally not expressed, but is rapidly and markedly induced in response to growth factors, tumor promoters, and cytokines. The abnormal expression of COX-2 appears to be a crucial step in the genesis of some cancers: we found that breast and colon tumors express high levels of this enzyme and that the prostaglandins stimulate tumor growth; and also are examining its role in programmed cell death (apoptosis). We are exploring the transcriptional and post-transcriptional regulation of this enzyme.  Current approaches include the use of transgenic mice with tissue-specific expression of the COX-2 enzyme and tumor cell lines that have inducible promoters for sense and antisense expression.

The lipid diacylglycerol (DAG) is a key intracellular messenger that activates protein kinases and leads to a variety of responses including cell growth. Many tumor cells have high levels of diacylglycerol and we have focused our studies on the basis for this change and the consequences of it. We have cloned cDNAs for a family of enzymes that metabolize DAG, the diacylglycerol kinases (DGKs), and are examining their role in the growth of normal and cancer cells.  The varied and specific roles of DGK family members suggest that each of the isoforms may play important signaling roles.  One of the enzymes is localized to the nucleus, fluctuates with the cell cycle, and may regulate DNA synthesis. Loss of a second DGK isoform confers resistance to seizures on genetically targeted transgenic mice. Knockout of a third DGK affects the development of the epithelial structures of mice and appears to be critical to signaling through the epidermal growth factor pathway. Current approaches include the use of stable over-expressing cell lines, knockout mice, and chimeric enzymes.

The phospholipid platelet activating factor (PAF) serves as an intercellular messenger that regulates inflammation.  PAF is potent (active below nM concentration), and its synthesis is tightly controlled; cells do not store it but make it in response to a stimulus. We have studied both the regulation of the synthesis of PAF and the route of its degradation. We purified the enzyme that degrades PAF, PAF acetylhydrolase, (PAF-AH), and isolated cDNA and genomic clones of this enzyme. Current studies examine the effects of PAF-AH in cellular metabolism and disease processes. In addition, these studies have led to novel findings in how cells interact and regulate gene expression, both to initiate, and resolve, inflammation.

 

References