TARGETING OF ADENOVIRUS E1A AND E4-ORF3 PROTEINS TO NUCLEAR MATRIX-ASSOCIATED PML BODIES

The PML protein was first identified as part of a fusion product with the retinoic acid receptor alpha (RAR alpha), resulting from the t(15; 17) chromosomal translocation associated with acute promyelocytic leuk emia (APL). It has been previously demonstrated that PML, which is tig htly bound to the nuclear matrix, concentrates in discrete subnuclear compartments that are disorganized in APL cells due to the expression of the PML-RAR alpha hybrid. Here we report that adenovirus infection causes a drastic redistribution of PML from spherical nuclear bodies i nto fibrous structures. The product encoded by adenovirus E4-ORF3 is s hown to be responsible for this reorganization and to colocalize with PML into these fibers. In addition, we demonstrate that E1A oncoprotei ns concentrate in the PML domains, both in infected and transiently tr ansfected cells, and that this association requires the conserved amin o acid motif (D)LXCXE, common to all viral oncoproteins that bind pRB or the related p107 and p130 proteins. The SV-40 large T antigen, anot her member of this oncoprotein family is also found in close associati on with the PML nuclear bodies. Taken together, the present data indic ate that the subnuclear domains containing PML represent a preferentia l target for DNA tumor viruses, and therefore suggest a more general i nvolvement of the PML nuclear bodies in oncogenic processes.