Phosphorylation of the cyclin-dependent kinase inhibitor p27 by upstream mitogenic signaling pathways regulates its stability, localization, and biological function. In human cancers, loss of the antiproliferative action of p27 can arise through reduced protein levels and/or cytoplasmic mislocalization, leading to increased cell proliferation and/or cell migration, respectively. Reduced p27 exp...

Phosphorylation of the cyclin-dependent kinase inhibitor p27 by upstream mitogenic signaling pathways regulates its stability, localization, and biological function. In human cancers, loss of the antiproliferative action of p27 can arise through reduced protein levels and/or cytoplasmic mislocalization, leading to increased cell proliferation and/or cell migration, respectively. Reduced p27 exp...

The activity of the cyclin-dependent kinase inhibitor p27 is controlled by its concentration and subcellular localization. However, the mechanisms that regulate its intracellular transport are poorly understood. Here we show that p27 is phosphorylated on Ser10 in vivo and that mutation of Ser10 to Ala inhibits p27 cytoplasmic relocalization in response to mitogenic stimulation. In contrast, a f...

Overexpression of ErbB-2yNeu has been causally associated with mammary epithelial transformation. Here we report that blockade of the epidermal growth factor receptor (EGFR) kinase with AG-1478 markedly delays breast tumor formation in mouse mammary tumor virus (MMTV)yNeu 1 MMTVytransforming growth factor a bigenic mice. This delay was associated with inhibition of EGFR and Neu signaling, reduc...

We have studied the role of the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1) in postnatal mammary gland morphogenesis. Based on its ability to negatively regulate cyclin/Cdk function, loss of p27 may result in unrestrained cellular proliferation. However, recent evidence about the stabilizing effect of p27 on cyclin D1-Cdk4 complexes suggests that p27 deficiency might recapitulate the hypo...

PURPOSE FGF-2 stimulates cell proliferation of rabbit corneal endothelial cells (rCECs) by degrading the cyclin-dependent kinase inhibitor p27(Kip1) (p27) through its phosphorylation mechanism. The authors investigated whether the cell proliferation of human CECs (hCECs) is also induced by FGF-2 stimulation through the p27 phosphorylation pathway. METHODS Expression and activation of protein ...

PURPOSE The cyclin-dependent kinase inhibitor p27(kip1) regulates cellular progression from G(1) to S phase. Several studies have shown that loss of p27(kip1) protein expression is associated with disease progression in various malignancies. The purpose of this study was to evaluate the subcellular localization of this cyclin-dependent kinase inhibitor in a large cohort of primary ovarian carci...

Heparin has growth inhibitory effects on pulmonary artery smooth muscle cell (PASMC) in vitro and in vivo. However, the mechanism has not been fully defined. In this study, we investigated the role of cyclin-dependent kinase inhibitors, p21 (p21) and p27 (p27), in the inhibitory effect of heparin on PASMC proliferation in vitro and on hypoxia-induced pulmonary hypertension in vivo using p21 and...

Enhanced Notch signaling contributes to uncontrolled cell growth and cell death resistance in cancer. Here, we demonstrate that in colorectal carcinoma cells the Notch1-dependent activation of cell cycle and proliferation is mediated by repression of the cyclin-dependent kinase inhibitor (CDKI) p27. The half-life of p27 significantly increased after siRNA‑mediated knockdown of Notch1. Notch1 de...

Oxidized LDL (OxLDL) induces proliferation in human umbilical vein endothelial cells (HUVEC). The influence of OxLDL on the cyclin-dependent kinase inhibitor p27(Kip1), on the activity of the small GTPase RhoA as a known regulator of p27(Kip1), and on resulting cell proliferation and hypertrophy was studied. HUVEC were stimulated with OxLDL (1 to 50 mug/ml). Proliferation was quantified by (3)H...