M. Fornaro et al., p27(kip1) acts as a downstream effector of and is coexpressed with the beta(1C) integrin in prostatic adenocarcinoma, J CLIN INV, 103(3), 1999, pp. 321-329
Integrins are a large family of transmembrane receptors that, in addition t
o mediating cell adhesion, modulate cell proliferation. The beta(1C) integr
in is an alternatively spliced variant of the beta(1) subfamily that contai
ns a unique 48-amino acid sequence in its cytoplasmic domain. We have shown
previously that in vitro beta(1C) inhibits cell proliferation and that in
vivo beta(1C) is expressed in nonproliferative, differentiated epithelium a
nd is selectively downregulated in prostatic adenocarcinoma. Here we show,
by immunohistochemistry and immunoblotting analysis, that beta(1C) is coexp
ressed in human prostate epithelial cells with the cell-cycle inhibitor p27
(kip1), the loss of which correlates with poor prognosis in prostate cancer
. In the 37 specimens analyzed, beta(1C) and p27(kip1) are concurrently exp
ressed in 93% of benign and 84%-91% of tumor prostate cells. Forced express
ion of beta(1C) in vitro is accompanied by an increase in p27(kip1) levels,
by inhibition of cyclin A-dependent kinase activity, and by increased asso
ciation of p27(kip1) with cyclin A. beta(1C) inhibitory effect on cell prol
iferation is completely prevented by p27(kip1) antisense, but not mismatch
oligonucleotides. beta(1C) expression does not affect either cyclin A or E
levels, or cyclin E-associated kinase activity, nor the mitogen-activated p
rotein (MAP) kinase pathway. These findings show a unique mechanism of cell
growth inhibition by integrins and point to beta(1C) as an upstream regula
tor of p27(kip1) expression and, therefore, a potential target for tumor su
ppression in prostate cancer.