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Vol. 10, Issue 5, 1609-1619, May 1999
Medical Research Council Membrane Biology Group, Department of
Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada
We have previously shown that human munc13 (hmunc13) is
up-regulated by hyperglycemia under in vitro conditions in human
mesangial cell cultures. The purpose of the present study was to
determine the cellular function of hmunc13. To do this, we have
investigated the subcellular localization of hmunc13 in a transiently
transfected renal cell line, opossum kidney cells. We have found that
hmunc13 is a cytoplasmic protein and is translocated to the Golgi
apparatus after phorbol ester stimulation. In addition, cells
transfected with hmunc13 demonstrate apoptosis after treatment with
phorbol ester, but cells transfected with an hmunc13 deletion mutant in which the diacylglycerol (C1) binding domain is absent exhibit no
change in intracellular distribution and no induction of apoptosis in
the presence of phorbol ester stimulation. We conclude that both the
diacylglycerol-induced translocation and the apoptosis represent
functional activity of hmunc13. We have also demonstrated that munc13-1
and munc13-2 are localized mainly to cortical epithelial cells in rat
kidney and both are overexpressed under conditions of hyperglycemia in
a streptozotocin-treated diabetic rat model. Taken together, our data
suggest that hmunc13 serves as a diacylglycerol-activated, PKC-independent signaling pathway capable of inducing apoptosis and
that this pathway may contribute to the renal cell complications of hyperglycemia.
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