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Vol. 303, Issue 1, 17-28, October 2002
-Isoform of Protein Kinase C Is Required for
Oxidant-Induced Disruption of Both the Microtubule Cytoskeleton and
Permeability Barrier of Intestinal Epithelia
Departments of Internal Medicine (Section of
Gastroenterology and Nutrition), Pharmacology, and Molecular
Physiology, Rush University Medical Center, Chicago, Illinois (A.B.,
J.Z.F., A.F., L.Z., A.K.); and Institute of Human Nutrition, Columbia
University, New York, New York (D.A.T.)
Using monolayers of intestinal (Caco-2) cells, we showed that oxidants
disassemble the microtubule cytoskeleton and disrupt barrier integrity
(permeability) (Banan et al., 2000a). Because exposure of our
parental cells to oxidants causes protein kinase C
(PKC)-
to be translocated to particulate fractions, we hypothesized that PKC- activation is required for these oxidant effects.
Monolayers of parental Caco-2 cells were incubated with
oxidant (H2O2) ± modulators. Other cells
were transfected with an inducible plasmid to stably overexpress
PKC- or with a dominant negative plasmid to stably inhibit the
activity of native PKC-. In parental
cells, oxidants caused translocation of PKC- to the particulate
(membrane + cytoskeletal) fractions, activation of PKC- isoform,
increases in monomeric (S1) tubulin and decreases in polymerized (S2)
tubulin, disruption of the microtubule cytoarchitecture, and loss of
barrier integrity (hyperpermeability). In transfected cells, induction of PKC- overexpression by itself (3.5-fold over its basal level) led
to oxidant-like disruptive effects. Disruption induced by PKC-
overexpression was potentiated by oxidants. Overexpressed PKC-
resided in particulate fractions, indicating its activation. Stable
inhibition of native PKC- activity (98%) by
dominant negative transfection substantially protected
against all measures of oxidative disruption. We conclude that 1)
oxidants induce loss of intestinal epithelial barrier integrity by
disassembling the microtubules in large part through the activation of
the PKC- isoform; and 2) overexpression and activation of PKC- is
by itself a sufficient condition for disruption of these cytoskeleton
and permeation pathways. Thus, PKC- activation may play a key role
in intestinal dysfunction in oxidant-induced diseases such as
inflammatory bowel disease.
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