Altered distribution of the promyelocytic leukemia-associated protein is associated with cellular senescence.
The disruption of the normal function and nuclear localization of the promyelocytic leukemia-associated protein (PML) may play a major role in the pathogenesis of acute promyelocytic leukemia. PML, which is concentrated in nuclear bodies (PML bodies), has been shown to have growth- and transformation-suppressive properties. In this study, we have examined the intranuclear distribution of PML in a conditionally immortalized human cell line (IDH4) in which both proliferation and immortalization are dependent on the presence of SV40-encoded large T-antigen (SV40T). Expression of SV40T is controlled by a dexamethasone (Dex)-inducible promotor. Suppression of SV40DT (Dex removal) in IDH4 cells causes G1 arrest and expression of the senescent phenotype. This is accompanied by a redistribution of PML in most cells from the usual pattern containing only spherical bodies to a pattern, containing large doughnut-like or fiber-like structures in addition to the spherical bodies. This change in pattern is reversed when phenotypically senescent IDH4 cells are stimulated to proliferate again by SV40T-induction. Moreover, we find that there is a similar change in the PML pattern between young and senescent or serum-starved young IMR90 human fibroblasts, from which IDH4 cells are derived. However, fewer serum-starved cells contain large PML bodies than senescent cells. Our observations suggest senescence, although it may be partly related to growth arrest. Using three-dimensional fluorescence digital imaging microscopy, we have found that the apparently doughnut-like PML structures have a cylindrical or egg-shaped form and that PML is concentrated to the outer shell of the structure.
Jiang
W Q
WQ
Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
Ringertz
N
N
D002455:Cell Division; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D003594:Cytoplasmic Granules / Q000378:metabolism / Q000648:ultrastructure*; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D013539:Simian virus 40; D014157:Transcription Factors / Q000032:analysis* / Q000648:ultrastructure; D025521:Tumor Suppressor Proteins
D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human