TMP53COMPMIX

Transcriptional mutagenesis in mammalian cell systems: p53 signaling as a probe of cellular effects

Coordinatore	KAROLINSKA INSTITUTET    more  Organization address address: Nobels Vag 5 city: STOCKHOLM postcode: 17177 contact info Titolo: Mr. Nome: Larsson Cognome: Per-Olof Email: send email Telefono: +46 8 524 87500 Fax: +46 8 33 69 81
Nazionalità Coordinatore	Sweden [SE]
Totale costo	100˙000 €
EC contributo	100˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2009-RG
Funding Scheme	MC-IRG
Anno di inizio	2010
Periodo (anno-mese-giorno)	2010-05-01   -   2014-04-30

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	KAROLINSKA INSTITUTET  Organization address address: Nobels Vag 5 city: STOCKHOLM postcode: 17177 contact info Titolo: Mr. Nome: Larsson Cognome: Per-Olof Email: send email Telefono: +46 8 524 87500 Fax: +46 8 33 69 81	SE (STOCKHOLM)	coordinator	100˙000.00

Mappa

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 Obiettivo del progetto (Objective)

'The process of misincorporation of incorrect bases into the nascent RNA as a result of DNA-lesion bypass by RNA polymerases during transcription is referred to as transcriptional mutagenesis (TM). Although this has been shown to alter the subsequent proteins function, the relative importance of TM in human health is virtually untouched. I propose to study the cellular effects and biological significance of TM using the tumor suppressor protein p53 as probe. The choice of p53 is based on its role as a guardian of the genome regulating life or death of cells. The objective will be achieved by developing novel expression constructs containing site-specific DNA damage yielding transcripts encoding mutant p53 protein. This will in part be done in a continued collaboration with my former post doctoral mentor at New York University, USA. The vectors will be transiently transfected into mammalian cells and the TM of p53 and the cellular effects on e.g. cell-cycle progression and viability studied. Furthermore, cellular model system will be utilized to study the potential effects of TM on the cellular response to a toxic insult. The model is based on the central role of p53 in the cellular response to DNA damages derived from carcinogenic polycyclic aromatic hydrocarbons (PAHs). Transfected cells exposed to complex PAH mixtures will be assayed with regard to relevant endpoints including; p53 down-stream signaling events and expression, cell cycle regulation and DNA repair. The results will be analyzed in relation to the p53 protein status. The use of PAH mixtures is motivated by the increasing interest by the European community in developing strategies for risk assessment of complex mixtures. The proposed project will take place at Karolinska Institutet, Sweden, ranked as one of the world’s leading biomedical universities with a strong European dimension, thus an excellent host in pursuing my Europe-oriented career plans.'

Introduzione (Teaser)

Chemical and physical agents represent a continuous threat to DNA integrity and cause DNA lesions. Despite the existence of DNA repair systems in cells, some lesions might not be removed and go on to interfere with DNA replication and transcription.