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Activity: Role
in
2 Integrin and Collagenase mRNA Expression
Department of Dermatology, School of Medicine, SUNY at Stony Brook, Stony Brook, New York 11794-8165
A three-dimensional collagen lattice can provide skin fibroblasts with a cell culture environment
that simulates normal dermis. Such a collagen matrix
environment regulates interstitial collagenase (type I
metalloproteinase [MMP-1], collagenase-1) and collagen receptor
2 subunit mRNA expression in both
unstimulated or platelet-derived growth factor-stimulated dermal fibroblasts (Xu, J., and R.A.F. Clark.
1996. J. Cell Biol. 132:239-249). Here we report that the collagen gel can signal protein kinase C (PKC)-
activation in human dermal fibroblasts. An in vitro kinase assay demonstrated that autophosphorylation of PKC-
immunoprecipitates was markedly increased by a collagen matrix. In contrast, no alteration in PKC-
protein levels or intracellular location was observed. DNA binding activity of nuclear factor
B (NF-
B), a downstream regulatory target of PKC-
, was also increased
by fibroblasts grown in collagen gel. The composition
of the NF-
B/Rel complexes that contained p50, was
not changed. The potential role of PKC-
in collagen gel-induced mRNA expression of collagen receptor
2
subunit and human fibroblast MMP-1 was assessed by
the following evidence. Increased levels of
2 and
MMP-1 mRNA in collagen gel-stimulated fibroblasts
were abrogated by bisindolylmaleimide GF 109203X
and calphostin C, chemical inhibitors for PKC, but retained when cells were depleted of 12-myristate 13-acetate (PMA)-inducible PKC isoforms by 24 h of pretreatment with phorbol PMA. Antisense oligonucleotides complementary to the 5
end of PKC-
mRNA sequences significantly reduced the collagen lattice-stimulated
2 and MMP-1 mRNA levels. Taken together,
these data indicate that PKC-
, a PKC isoform not inducible by PMA or diacylglycerol, is a component of
collagen matrix stimulatory pathway for
2 and MMP-1
mRNA expression. Thus, a three-dimensional collagen
lattice maintains the dermal fibroblast phenotype, in
part, through the activation of PKC-
.
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