Activation of Erk1/Erk2 and transiently increased p53 levels together may account for p21 expression associated with phorbol ester-induced transient growth inhibition in HepG2 cells.

In HepG2 cells grown in the presence of serum, enhanced Raf-activation correlated with transient growth inhibition. The activation of Raf was increased either by the phorbol ester-induced activation of protein kinase C (PKC) or by the addition of the PKC inhibitor bisindolylmaleimide I (BIM). Either of these treatments increased the cellular levels of p21 by an Erk1/Erk2 MAP kinase cascade-dependent way, since this increase was prevented by the MEK-inhibitor PD98059.

The role of protein kinase C in the development of the complications of diabetes.

Diabetes mellitus produces a state of chronic hyperglycemia which in turn leads to the development of severe complications including retinopathy, nephropathy, neuropathy, and atherosclerosis. Many different mechanisms have been put forward to attempt to explain how glucose elevations can damage these various organ systems. Protein kinase C activation is one of the sequelae of hyperglycemia and is thought to play a role in the development of diabetic complications.

Protein kinase C decreases the hepatocyte growth factor-induced activation of Erk1/Erk2 MAP kinases.

HGF and phorbol ester induce the scattering of HepG2 cells. Recently, we have reported that the motility and morphological responses that accompany this process require the activation of Erk1/Erk2 MAP kinases, and phosphatidylinositol 3-kinase contributes to the activation of Erk1/Erk2 in HGF-induced cells. The cell scattering-associated appearance of a high-M(r) (>300 kDa) protein pair has also been observed, and has been proven to be a sensitive marker of the intensity of Erk1/Erk2 activation.

Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes.

Activation of protein kinase C (PKC) is implicated as an important mechanism by which diabetes causes vascular complications. We have recently shown that a PKC beta inhibitor ameliorates not only early diabetes-induced glomerular dysfunction such as glomerular hyperfiltration and albuminuria, but also overexpression of glomerular mRNA for transforming growth factor beta1 (TGF-beta1) and extracellular matrix (ECM) proteins in streptozotocin-induced diabetic rats, a model for type 1 diabetes. In this study, we examined the long-term effects of a PKC beta inhibitor on glomerular histology as well as on biochemical and functional abnormalities in glomeruli of db/db mice, a model for type 2 diabetes.

Phosphatidylinositol 3-kinase contributes to Erk1/Erk2 MAP kinase activation associated with hepatocyte growth factor-induced cell scattering.

MAP kinase cascade-dependent responses were investigated during scattering of HepG2 human hepatoma cells stimulated by HGF or phorbol ester. Inhibition of phosphatidylinositol 3-kinase with LY294002 prevented completely the dissociation of cells. Inhibition of MAP kinase kinase (MEK) with PD98059 prevented the development of characteristic morphological changes associated with cell migration.