G. Radeva et al., OVEREXPRESSION OF THE INTEGRIN-LINKED KINASE PROMOTES ANCHORAGE-INDEPENDENT CELL-CYCLE PROGRESSION, The Journal of biological chemistry, 272(21), 1997, pp. 13937-13944
Cell adhesion to substratum has been shown to regulate cyclin A expres
sion as well as cyclin D- and E-dependent kinases, the latter via the
up-regulation of cyclin DI and the down-regulation of cyclin-Cdk inhib
itors p21 and p27, respectively. This adhesion-dependent regulation of
cell cycle is thought to be mediated by integrins. Here we demonstrat
e that stable transfection and overexpression of the integrin-linked k
inase (ILK), which interacts with the beta 1 and beta 3 integrin cytop
lasmic domains, induces anchorage-independent cell cycle progression b
ut not serum independent growth of rat intestinal epithelial cells (IE
C18). ILK overexpression results in increased expression of cyclin D1,
activation of Cdk4 and cyclin E-associated kinases, and hyperphosphor
ylation of the retinoblastoma protein, In addition, ILK overexpression
results in the expression of p21 and p27 Cdk inhibitors with altered
electrophoretic mobilities, with the p27 from ILK-overexpressing cells
having reduced inhibitory activity, The transfer of serum-exposed IEC
18 cells from adherent cultures to suspension cultures results in a ra
pid down-regulation of expression of cyclin DI and cyclin A proteins a
s well as in retinoblastoma protein dephosphorylation. In marked contr
ast, transfer of ILK overexpressing cells from adherent to suspension
cultures results in continued high levels of expression of cyclin D1 a
nd cyclin A proteins, and a substantial proportion of the retinoblasto
ma protein remains in a hyperphosphorylated state, These results indic
ate that, when overexpressed, ILK induces signaling pathways resulting
in the stimulation of G(1)/S cyclin-Cdk activities, which are normall
y regulated by cell adhesion and integrin engagement.