title: The nucleolus directly regulates p53 export and degradation.
abstract: The correlation between stress-induced nucleolar disruption and abrogation of p53 degradation is evident after a wide variety of cellular stresses. This link may be caused by steps in p53 regulation occurring in nucleoli, as suggested by some biochemical evidence. Alternatively, nucleolar disruption also causes redistribution of nucleolar proteins, potentially altering their interactions with p53 and/or MDM2. This raises the fundamental question of whether the nucleolus controls p53 directly, i.e., as a site where p53 regulatory processes occur, or indirectly, i.e., by determining the cellular localization of p53/MDM2-interacting factors. In this work, transport experiments based on heterokaryons, photobleaching, and micronucleation demonstrate that p53 regulatory events are directly regulated by nucleoli and are dependent on intact nucleolar structure and function. Subcellular fractionation and nucleolar isolation revealed a distribution of ubiquitylated p53 that supports these findings. In addition, our results indicate that p53 is exported by two pathways: one stress sensitive and one stress insensitive, the latter being regulated by activities present in the nucleolus.
authors: p53/MDM2 Research Group, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3GA, England, UK.
authors: Mark T
authors: MT
authors: Boyd
authors: Nikolina
authors: N
authors: Vlatkovic
authors: Carlos P
authors: CP
authors: Rubbi
mesh_terms: D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002459:Cell Fusion; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000187:drug effects / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology / Q000528:radiation effects; D003703:Demecolcine / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D042581:Intranuclear Space / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D009697:Nucleolus Organizer Region / Q000187:drug effects; D038761:Photobleaching; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D005231:Fatty Acids, Unsaturated; D007976:Leupeptins; D011993:Recombinant Fusion Proteins; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C485184:enhanced green fluorescent protein; C027624:ribosomal protein L11; D049452:Green Fluorescent Proteins; D003513:Cycloheximide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C038753:leptomycin B; D003703:Demecolcine