Search

The modification of Gelatinase A by neutrophil elastase depends on the presence of matrix components. In the absence of gelatin, Gelatinase A is proteolytically modified by neutrophil elastase by the hydrolysis of bonds in the fibro-nectin like gelatin binding domain. However in the presence of gelatin, cleavage takes place in the carboxyl-terminal domain and a truncated active form gelatinase is formed. Gelatinase A is a metalloproteinase which is overexpressed in tumor cells.

Lens regeneration in adult newts is always initiated from the dorsal iris by transdifferentiation of the pigment epithelial cells. One of the most important early events should be the ability of pigment epithelial cells to dedifferentiate and re-enter the cell cycle. As a first step in an attempt to study this event, we have decided to examine the effects of a cyclin-dependent kinase-2 inhibitor on lens regeneration. At the appropriate concentration, this inhibitor completely abolished the ability of pigment epithelial cells to form a new lens, but it did not stop them from dedifferentiating and forming a small lens vesicle. The effects of this inhibitor seem to be mediated by its opposite effects on cell proliferation and apoptosis. The inhibitor significantly reduced cell proliferation and enhanced apoptosis of pigment epithelial cells both in vitro and in vivo and of the regenerating lens in vivo. [ABSTRACT FROM AUTHOR]

Here, we report the identification and characterization of five ortho-quinone inhibitors of PTPα. We observed that the potency of these compounds in biochemical assays was markedly enhanced by the presence of DTT. A kinetic analysis suggested that they were functioning as irreversible inhibitors and that the inhibition was targeted to the catalytic site of PTPα. The inhibition observed by these compounds was sensitive to superoxide dismutase and catalase, suggesting that reactive oxygen species may be mediators of their inhibition. We observed that in the presence of DTT, these compounds would produce up to 2.5 mM hydrogen peroxide (H2O2). The levels of H2O2 produced were sufficient to completely inactivate PTPα. In contrast, without a reducing agent the compounds did not generate H2O2 and showed little activity towards PTPα. In addition, these compounds inhibited PTPα-dependent cell spreading in NIH 3T3 cells at concentrations that were similar to their activity in biochemical assays. The biological implications of these results are discussed as they support growing evidence that H2O2 is a key regulator of PTPs. [Copyright &y& Elsevier]

SU9516 is a 3-substituted indolinone compound with demonstrated potent and selective inhibition toward cyclin dependent kinases (cdks). Here, we describe the kinetic characterization of this inhibition with respect to cdk2, 1, and 4, along with the crystal structure in complex with cdk2. The molecule is competitive with respect to ATP for cdk2/cyclin A, with a Ki value of 0.031 μM. Similarly, SU9516 inhibits cdk2/cyclin E and cdk1/cyclin B1 in an ATP-competitive manner, although at a 2- to 8-fold reduced potency. In contrast, the compound exhibited non-competitive inhibition with respect to ATP toward cdk4/cyclin D1, with a 45-fold reduced potency. The X-ray crystal structure of SU9516 bound to cdk2 revealed interactions between the molecule and Leu83 and Glu81 of the kinase. This study should aid in the development of more potent and selective cdk inhibitors for potential therapeutic agents. [Copyright &y& Elsevier]