Regulation of DNA polymerase beta by the LMP1 oncoprotein of EBV through the nuclear factor-kappaB pathway. - Université Toulouse 3 Accéder directement au contenu
Article Dans Une Revue Cancer Research Année : 2009

Regulation of DNA polymerase beta by the LMP1 oncoprotein of EBV through the nuclear factor-kappaB pathway.

Résumé

The repair DNA polymerase beta (Polbeta), when overexpressed, plays a critical role in generating genetic instability via its interference with the genomic replication program. Up-regulation of Polbeta has been reported in many tumor types that exhibit genetic aberrations, including EBV-related B-cell lymphomas. However, the mechanisms responsible for its overexpression have never been examined. Here, we report that both expression and activity of Polbeta, in EBV-immortalized B cells, are induced by several natural genetic variants of LMP1, an oncoprotein associated with the vast majority of EBV-related tumors. Conversely, we found that the expression of Polbeta decreased when LMP1 signaling was down-regulated by a dominant negative of LMP1 or an inhibitor of the nuclear factor-kappaB (NF-kappaB) pathway, the main transduction pathway activated by LMP1, strongly supporting a role of NF-kappaB in the LMP1-mediated Polbeta regulation. Using electrophoretic mobility shift assay experiments from several EBV-immortalized B-cell nuclear extracts, we identified an LMP1-dependent p50/c-Rel heterodimer on a proximal kappaB binding site (-211 to -199nt) of the Polbeta promoter. This result was correlated with a specific Polbeta kappaB transcriptional activity. Taken together, our data enlighten a new mechanism responsible for Polbeta overexpression in EBV-infected cells, mediated by LMP1 and dependent on NF-kappaB activation.

Domaines

Immunologie

Dates et versions

hal-00397988 , version 1 (23-06-2009)

Identifiants

Citer

Nathalie Faumont, Christophe Le Clorennec, Pierre Teira, Gauthier Goormachtigh, Jean Coll, et al.. Regulation of DNA polymerase beta by the LMP1 oncoprotein of EBV through the nuclear factor-kappaB pathway.. Cancer Research, 2009, 69 (12), pp.5177-85. ⟨10.1158/0008-5472.CAN-08-2866⟩. ⟨hal-00397988⟩
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