Huntsman Cancer Institute
2000 Circle of Hope
Salt Lake City, UT 84112
Tel (801) 585-3401
Fax (801) 585-6345
stephen.prescott
@hci.utah.edu
Prescott Publications
Prescott Lab Members
Funding Sources
Prescott Lab Alumni
DGKs in cell growth control
A focus of interest in lipid-based signaling in the Prescott lab is the
examination of the fate of the intracellular messenger, diacylglycerol
(DAG). DAG accumulates transiently in cells exposed to growth factors
or other stimuli. Elevated DAG mediates diverse cellular responses such
as growth and differentiation by virtue of binding to and activating protein
kinase C. This process can be activated inappropriately in cancer cells,
as these cells often have high levels of diacylglycerol.
The lab has provided key insights into the regulation of this process
by identifying and cloning several genes that encode diacylglycerol kinases,
enzymes that shut off the DAG activation signal. Further, they have shown
that one of the DGK isoforms has a novel mechanism for shuttling in and
out of the nucleus and that while in the nucleus it suppresses growth
signals. The discovery of this large family of lipid kinases has opened
many new studies of signaling mechanisms and their cellular consequences.
COX-2 and cancer
The Prescott lab has been a leader in studies of prostaglandins and related
compounds. In experiments examining the regulation of cell growth, Prescott’s
group discovered marked shifts in the biochemical fate of arachidonic
acid, which led to the identification and cloning of the human COX-2 gene.
The lab was the first to clone an active form of this human gene. Studies
have shown that the COX-2 enzyme is the rate-limiting step in colon carcinogenesis.
The COX-2 enzyme is now the target for new therapeutic drugs.
Prescott's group examined the COX-2 gene for polymorphisms that alter
inherited predisposition to colon cancer and showed that expression of
the gene is influenced strongly by post-transcriptional mechanisms that
may be a central component of carcinogenesis. In addition, the lab showed
that COX-2 acts pro-neoplastically, not only through production of prostaglandins,
but by diverting unesterified arachidonic acid that would otherwise signal
to promote cell death. Thus, this work on lipid messengers has led to
new mechanistic insights and practical applications in a common cancer.
Molecular basis of inflammation
The Prescott lab has examined the role of a family of phospholipids that
initiate inflammation and allergy. The lab showed that when endothelial
cells are activated by a variety of inflammatory mediators, their cell
surface changes to one that is adhesive for leukocytes. This finding explained
how the inflammatory response could be localized to an appropriate area
and not result in a systemic response. Further studies uncovered a novel,
multi-step mechanism: endothelial cells translocate a protein, P-selectin,
to their surface and this protein "tethers" leukocytes to the
endothelial cells, but does not fully activate them. Simultaneously, the
endothelial cells synthesize a lipid mediator, platelet-activating factor
(PAF), which completes the activation of the leukocyte. This mechanism
provides an editing mechanism that prevents the inappropriate activation
or recruitment of leukocytes since all the components must be present
to achieve a complete response.
The regulated process can be mimicked by a non-enzymatic pathway that
results from the production of oxidized phospholipids which can bind to
the PAF receptor and reproduce its actions. The Prescott group described
this process and carried out detailed chemical analysis of the structure
of these phospholipids, which have been shown to occur in inflammatory
syndromes and in atherosclerosis.
The Prescott lab has also defined how PAF and the oxidized phospholipids are degraded, resulting in a termination of the inflammation signal. The lab purified, cloned, and characterized a specific plasma phospholipase, PAF-AH, and showed that it is synthesized and secreted by macrophages. The PAF-AH recombinant enzyme has marked anti-inflammatory properties in animal models and is currently undergoing clinical trials for use in severe, acute inflammation.