Suppression of cellular proliferation and invasion by the concerted lipid and protein phosphatase activities of PTEN.

PTEN is a tumour suppressor with phosphatase activity in vitro against both lipids and proteins and other potential non-enzymatic mechanisms of action. Although the importance of PTEN's lipid phosphatase activity in regulating the PI3K signalling pathway is recognized, the significance of PTEN's other mechanisms of action is currently unclear. In this study, we describe the systematic identification of a PTEN mutant, PTEN Y138L, with activity against lipid, but not soluble substrates. Using this mutant, we provide evidence for the interfacial activation of PTEN against lipid substrates. We also show that when re-expressed at physiological levels in PTEN null U87MG glioblastoma cells, the protein phosphatase activity of PTEN is not required to regulate cellular PtdInsP(3) levels or the downstream protein kinase Akt/PKB. Finally, in three-dimensional Matrigel cultures of U87MG cells similarly re-expressing PTEN mutants, both the protein and lipid phosphatase activities were required to inhibit invasion, but either activity alone significantly inhibited proliferation, albeit only weakly for the protein phosphatase activity. Our data provide a novel tool to address the significance of PTEN's separable lipid and protein phosphatase activities and suggest that both activities suppress proliferation and together suppress invasion.

Establishing a breast clinic in a developing country: effect of a collaborative project.

This paper describes a project funded by DFID (Department of International Development of the United Kingdom) for the establishment of breast clinic in an oncological center in a developing country, Sri Lanka. In Sri Lanka the commonest female cancer is breast cancer, with an incidence of 7.7 per 100,000. The project utilized a link with an existing breast clinic at the Royal Marsden UK. The principal methods used for establishing the clinic included, assessment of possible barriers by the exchange of senior staff, the development of guidelines, and regular review of progress by both link partners. As a result of these interactions, the first breast clinic in Sri Lanka was established. In has shown results in an increase in the pick up rate of new patients with breast cancer.

Morton Medal Lecture. New insights into the roles of phosphoinositides and inositol polyphosphates in yeast.

During the past half century, we have progressed from simply viewing myo -inositol-containing glycerophospholipids as quantitatively minor membrane constituents to the present, very striking, situation in which more and more important cellular functions are being assigned to a plethora of phosphorylated derivatives of inositol and phosphatidylinositol. Two such examples are discussed briefly: the activation by environmental stresses of the single phosphoinositidase C of yeast, which is related to the phospholipase C delta s of other eukaryotes, and the involvement of PtdIns(3,5) P (2) in endomembrane trafficking.

Paraoxon and parathion hydrolysis by aqueous molybdenocene dichloride (Cp2MoCl2): first reported pesticide hydrolysis by an organometallic complex.

We report the first case of an organometallic complex that effectively hydrolyzes the organophosphate pesticides parathion and paraoxon. The complex is the water-soluble compound bis(eta 5-cyclopentadienyl)molybdenum(IV) dichloride (1), which hydrolyzes parathion to produce ethanol and deethyl parathion in a biphasic reaction in D2O. Rate accelerations were 130 and 10(5) at pH 7 and 3, respectively. Paraoxon is readily hydrolyzed by 1 to yield p-nitrophenol and diethyl phosphate with rate accelerations of 2300 and 27 at pH 7 and 3, respectively. Kinetic data for paraoxon hydrolysis by 1 are consistent with a process that involves intermolecular (delta S++ = -49 +/- 10 eu) hydroxide attack on the phosphate triester in which the aquated 1 serves as a coordinated Lewis acid that activates the organophosphate. Interestingly parathion hydrolysis by 1 occurs via nucleophilic attack at the alpha-carbon of the phosphorothioate pesticide that involves C-O bond cleavage. These parathion results represent one of the few cases of this type of unusual hydrolytic chemistry and the first case of an organometallic complex that accelerates organophosphate pesticide hydrolysis.