Dr. DeBose-Boyd received his graduate training in the laboratory
of Dr. Richard D. Cummings at the University of Oklahoma Health
Sciences Center in Oklahoma City, OK. After defending a thesis
entitled "Identification, characterization, and molecular cloning
of a1,3 fucosyltransferases in helminthes,” he joined the laboratory
of Drs. Michael S. Brown and Joseph L. Goldstein at the University
of Texas Southwestern Medical Center in Dallas, TX. The overall
research goal of Dr. DeBose-Boyd's post-doctoral studies was
to better understand the molecular basis of lipid homeostasis
in animal cells, which is mediated by membrane-bound transcription
factors termed sterol regulatory element-binding proteins (SREBPs).
Specifically, he sought to determine how the protein SCAP (SREBP
cleavage-activating protein) facilitates the release of active
SREBP fragments from membranes when cells are deprived of cholesterol.
Dr. DeBose-Boyd began his work by characterizing a mutant cell
line in which the SCAP gene was inactivated. Initially, he demonstrated
that SCAP is absolutely required for SREBP activation and was
restored in mutant cells upon introduction of SCAP by transfection.
The availability of the SCAP-deficient cells allowed Dr. DeBose-Boyd
to further investigate the function of SCAP. He demonstrated
that treatment of cells with brefeldin A, a drug that causes
redistribution of Golgi proteins to the ER, caused SREBP proteases
to translocate to the ER and abrogated the need for transport
of SREBP to the Golgi. In addition, brefeldin A restored SREBP
processing in SCAP-deficient cells. The results of these studies
led to a model in which SCAP escorts SREBPs from the ER
to the Golgi apparatus in sterol-deprived cells and recycles
back to the ER following SREBP release by Golgi-localized proteases.
Sterols block SREBP processing by preventing the transport of
the SCAP-SREBP complex to the Golgi. These studies have had
profound effects on the understanding of lipid homeostasis in
animal cells. On the cellular level, the demonstration that
SCAP functions to transport SREBPs from the ER to the Golgi
represents a novel means of transcriptional factor activation.
Transport-dependent proteolysis of SREBPs explains how signals
generated in distinct cellular compartments can be relayed to
the nucleus, thus laying the groundwork for the study of other
membrane-bound transcription factors.