Identification and Characterization of Mechanism of Action of P61-E7, a Novel Phosphine Catalysis-Based Inhibitor of Geranylgeranyltransferase-I

Small molecule inhibitors of protein geranylgeranyltransferase-I (GGTase-I) provide a promising type of anticancer drugs. Here, we first report the identification of a novel tetrahydropyridine scaffold compound, P61-E7, and define effects of this compound on pancreatic cancer cells. P61-E7 was identified from a library of allenoate-derived compounds made through phosphine-catalyzed annulation reactions. P61-E7 inhibits protein geranylgeranylation and blocks membrane association of geranylgeranylated proteins. P61-E7 is effective at inhibiting both cell proliferation and cell cycle progression, and it induces high p21CIP1/WAF1 level in human cancer cells. P61-E7 also increases p27Kip1 protein level and inhibits phosphorylation of p27Kip1 on Thr187. We also report that P61-E7 treatment of Panc-1 cells causes cell rounding, disrupts actin cytoskeleton organization, abolishes focal adhesion assembly and inhibits anchorage independent growth. Because the cellular effects observed pointed to the involvement of RhoA, a geranylgeranylated small GTPase protein shown to influence a number of cellular processes including actin stress fiber organization, cell adhesion and cell proliferation, we have evaluated the significance of the inhibition of RhoA geranylgeranylation on the cellular effects of inhibitors of GGTase-I (GGTIs). Stable expression of farnesylated RhoA mutant (RhoA-F) results in partial resistance to the anti-proliferative effect of P61-E7 and prevents induction of p21CIP1/WAF1 and p27Kip1 by P61-E7 in Panc-1 cells. Moreover, stable expression of RhoA-F rescues Panc-1 cells from cell rounding and inhibition of focal adhesion formation caused by P61-E7. Taken together, these findings suggest that P61-E7 is a promising GGTI compound and that RhoA is an important target of P61-E7 in Panc-1 pancreatic cancer cells

Changing Housing for Elderly People and Co-ordination Issues in Europe

The inter-sectoral policy systems of housing for elderly people in the EU-countries change with the implementation of ageing in place and by general processes of modernisation of society and welfare state. For implementation of the innovations the relevance of co-ordination between the sector housing, care and social services depends on the state of development of the sectors in a country. However, modernisation threatens co-ordination by decentralisation, privatisation and transfer of choices and responsibilities to the individual. This paper is an international comparative study describing how countries of the European Union are dealing with the topic of co-ordination. Nowadays especially policy actors at the regional and local level have the responsibility for inter-sectoral co-ordination. Looking at the practices of these actors the development of a shared vision on ageing in place seems to be very important. Central government should facilitate this approach and control the results. The term 'managed co-operation' describes very well this new way of management of co-ordination

New public management and accounting in a Fiji telecommunications company

The aim of this article is to investigate tension between the implementation of new public management and associated accounting technologies in the Fiji telecommunication sector and the indigenous Fijian culture and political structure. In doing so, the article contrasts the economic-based reforms of the telecommunications sector (from 1990), with the traditional social relations that were exercised post-independence (1970 onwards). This research aim is achieved by focusing on archival documents and interviews with those involved in Fiji telecommunications. We illustrate how the use of new public management concepts replaced traditional social relations with the disciplinary technologies of modern capitalism but were also altered as a result of these social relations. In the Fiji Telecommunications company, the cultural conflicts and political influences led to the new public management process being resisted and modified to reduce the tension between economic and social relation