ARSSIGBYP38CASCADE · Biochemical and genetic characterisation of the p38 MAPK cascade that mediates arsenite signalling in human osteosarcoma cells
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2004-04-01 → 2006-03-31
- EU contribution
- €150,237
- Participants
- 1
- Scheme
- EIF
Lines connect the coordinator with its partners.
Results in brief
Final Activity Report Summary - ARSSIGBYP38CASCADE (Biochemical and genetic characterisation of the p38 MAPK cascade that mediates arsenite signalling in human osteosarcoma cells)
The project aimed to characterise the network around the mitogen-activated protein kinase p38 that mediates gene activation by arsenite in osteosarcoma cells. The biochemical portion gave hints at a modular organisation of this pathway without providing proof sufficiently definitive for a scientific publication. In contrast, the genetic studies, using the recently develop technology of RNA interference, clearly identified the kinase MSK1 as the major partner of p38 in activating the genetic program of osteosarcoma cells to the tumour promoter and industrial pollutant arsenite.
Data: CORDIS, © European Union
Project objective
Arsenic contamination from both natural and industrial sources is a significant public health problem. Arsenite, the trivalent form of arsenic, is a strong tumour promoter associated with multiple types of cancer. Paradoxically, arsenite is also effective in treating acute promyelocytic leukemia.The exact mechanism of arsenite activity is still unclear; however, it strongly induces three major intracellular signalling pathways, the ERK, SAPK and p38 MARK cascades, that control gene expression via the transcriptional regulator AP-1.Within the ERK and SAPK cascades, specificity is conferred by organisation into distinguishable signalling modules assembled into large molecular complexes. Our recent data indicate that, in human osteosarcoma cells, the p38 pathway also contains different signalling modules activated selectively by arsenite and the antibiotic anisomycin.This project will- characterise the molecular organisation of the p38 cascade activated by arsenite in cancer-derived cell lines and- use the novel genetic technique of RNA interference to selectively inactivate arsenite-indeed intracellular signalling.We will use biochemistry and molecular biology techniques to analyse the molecular assemblies that mediate this selectivity within the p38 cascade. To address the role of the p38 cascade in the cellular response to arsenite, components of this cascade will be down-regulated using RNA interference.These siRNAs will target different isoforms óf p38 and its activating kinases MKKs 3, 3b and 6. We will assess the effect of their elimination on the induction of genes encoding components of AP-1, such as c-fos, c-jun, andjunB.Taken together, these two approaches will further our understanding of the mechanism by which arsenite can exert both carcinogenic and therapeutic effects, thereby opening potential avenues for blocking or potentiating arsenite activity.
Original text from CORDIS.
Participants
- CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE · PARISCoordinatorFrance
Links
Data: CORDIS, © European Union