Integrins may play important roles in many cellular events, such as cell proliferation, differentiation, and apoptosis. We showed previously that overexpression of
integrin beta1 inhibits cell proliferation in SMMC-7721 cells. Here we reported that one of the
cyclin-dependent kinase (CDK) inhibitors, p27(Kip1) was involved in proliferation-inhibition induced by overexpression of
integrin beta1. Overexpression of
integrin beta1 upregulated p27(Kip1) at the
protein level, but not
mRNA level. The knock-down of p27(Kip1) expression restored cell growth in
integrin beta1-overexpressing cells.
Cycloheximide (Chx) treatment and pulse-chase experiments revealed that overexpression of
integrin beta1 prolonged the half-life of p27(Kip1) by inhibiting its degradation.
Proteasome inhibitor (
MG132) treatment of the cells indicated that
proteasome mediated degradation of p27, and Skp2-dependent degradation might be prevented. Overexpression of
integrin beta1 decreased Skp2 at
mRNA level, which was regulated by cell adhesion and the subsequent adhesion-dependent signaling. Overexpression of
integrin beta1 reduced cell adhesion, accordingly, inactivated the
phosphoinositide 3-kinase (PI3K) signaling. PI3K inhibitor
LY294002 upregulated p27(Kip1) at post-translational level and downregulate Skp2 at
mRNA level, which could mimic the effects of
integrin beta1 overexpression on p27(Kip1) and Skp2. Together, these results suggested that overexpression of
integrin beta1 inhibited cell proliferation by preventing the Skp2-dependent degradation of p27(Kip1) via PI3K pathway.