Non-activated p53 co-localizes with sites of transcription within both the nucleoplasm and the nucleolus

Rubbi, Carlos P.; Milner, Jo

doi:10.1038/sj.onc.1203378

Cited by 73 publications

(56 citation statements)

References 42 publications

(42 reference statements)

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“…Within the nucleus, p53 has been reported to be associated with at least three subnuclear compartments including the nucleolus, promyelocytic leukemia bodies and cajal bodies (Mogaki et al, 1993;Benninghoff et al, 1999;Rubbi and Milner, 2000;Horky et al, 2001;Klibanov et al, 2001;Wesierska-Gadek et al, 2002;Young et al, 2002;Zimber et al, 2004). Approximately half of nuclear p53 is soluble, whereas the remainder associates with nuclear structures (Zerrahn et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Energy-dependent nucleolar localization of p53 in vitro requires two discrete regions within the p53 carboxyl terminus

et al. 2007

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The p53 tumor suppressor is a nucleocytoplasmic shuttling protein that is found predominantly in the nucleus of cells. In addition to mutation, abnormal p53 cellular localization is one of the mechanisms that inactivate p53 function. To further understand features of p53 that contribute to the regulation of its trafficking within the cell, we analysed the subnuclear localization of wild-type and mutant p53 in human cells that were either permeabilized with detergent or treated with the proteasome inhibitor MG132. We, here, show that either endogenously expressed or exogenously added p53 protein localizes to the nucleolus in detergent-permeabilized cells in a concentration-and ATP hydrolysis-dependent manner. Two discrete regions within the carboxyl terminus of p53 are essential for nucleolar localization in permeabilized cells. Similarly, localization of p53 to the nucleolus after proteasome inhibition in unpermeabilized cells requires sequences within the carboxyl terminus of p53. Interestingly, genotoxic stress markedly decreases the association of p53 with the nucleolus, and phosphorylation of p53 at S392, a site that is modified by such stress, partially impairs its nucleolar localization. The possible significance of these findings is discussed.

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Section: Introductionmentioning

confidence: 99%

Energy-dependent nucleolar localization of p53 in vitro requires two discrete regions within the p53 carboxyl terminus

et al. 2007

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“…However, it has become increasingly clear that they actively participate in the apoptosis process. Non activated p53 significantly localizes to nucleoli and is believed to monitor sites of active transcriptional activity, 33 and UBF has been shown to be cleaved by caspases early during apoptosis. 34 It was demonstrated that UBF moves out of nucleoli during apoptosis whereas other nucleolar protein such as B23 stay within these structures.…”

Section: Discussionmentioning

confidence: 99%

Nuclear localization of DEDD leads to caspase-6 activation through its death effector domain and inhibition of RNA polymerase I dependent transcription

et al. 2001

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The death effector domain (DED) is a protein/protein interaction domain only found in proteins that are involved in apoptosis signaling. DEDD is a novel apoptosis signaling molecule that carries an N-terminal DED with complete sequence identity between the murine, rat, bovine and human domains. We previously identified two nuclear localization signals (NLS) responsible for DEDDs nuclear localization when transiently expressed. Using a new anti-DEDD antibody that allows us to stain endogenous DEDD in immunofluorescence microscopy we now detect a significant amount of DEDD in nucleoli of all cells tested. When overexpressed, DEDD localizes to nucleoli-like structures, activates caspase-6 and specifically inhibits RNA polymerase I (Pol I) dependent transcription in vivo as shown by blockage of BrUTP incorporation. The DED in DEDD is sufficient for its DNA binding, caspase-6 activating and Pol I specific transcriptional repressor activity. We have identified a third NLS in DEDD and only mutation of all three NLS generated a protein, DEDDDNLS1-3, that mainly localized to the cytoplasm. This protein no longer induced apoptosis, indicating that in contrast to other DED proteins, such as FADD, caspase-8 or c-FLIP, DEDD induces apoptosis from within the nucleus. This effect is abolished when specific point mutations are made within the DED. The DED in DEDD therefore represents a novel domain that is structurally similar to other DEDs but functionally different from classical DEDs found in FADD or caspase-8.

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“…This could be a mechanism for regulating p53 function, potentially by physical sequestration of p53 in a cellular compartment that inhibits p53 function. Nucleolar accumulation of p53 has recently been shown (41,42). SMN can also accumulate within the nucleolus of adult neuronal cells and all fetal cell types (31, 32).…”

Section: Smn Complexes With P53 In Vivo and Inmentioning

confidence: 99%

A Direct Interaction between the Survival Motor Neuron Protein and p53 and Its Relationship to Spinal Muscular Atrophy

Young¹,

Day²,

Zhou³

et al. 2002

Journal of Biological Chemistry

112

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Mutations in the SMN1 (survival motor neuron 1) gene cause spinal muscular atrophy (SMA). We now show that SMN protein, the SMN1 gene product, interacts directly with the tumor suppressor protein, p53. Pathogenic missense mutations in SMN reduce both self-association and p53 binding by SMN, and the extent of the reductions correlate with disease severity. The inactive, truncated form of SMN produced by the SMN2 gene in SMA patients fails to bind p53 efficiently. SMN and p53 colocalize in nuclear Cajal bodies, but p53 redistributes to the nucleolus in fibroblasts from SMA patients. These results suggest a functional interaction between SMN and p53, and the potential for apoptosis when this interaction is impaired may explain motor neuron death in SMA.Spinal muscular atrophy is a neurodegenerative disorder characterized by loss of the ␣-motor neurons of the spinal cord, resulting in progressive atrophy of the voluntary muscles of the limb and trunk (1). There are three forms of the childhood disease, types I, II, and III, with type I being the most severe. All three forms are due to mutations of the telomeric copy of the SMN1 (survival motor neuron 1) gene (2). The centromeric copy of the SMN gene (SMN2) differs from SMN1 by only 11 nucleotides (2, 3). One of these is a C/T transition located in exon 7 and results in different pre-mRNA splicing patterns; SMN1 produces mainly full-length product, whereas the majority of SMN2-derived transcripts lack exon 7, SMN⌬7 (2-4).SMN is a ubiquitously expressed protein localized within the cytoplasm and the nucleus (2). Nuclear SMN localizes within Cajal bodies (5). Cajal bodies are defined by the presence of p80 coilin (6). Although the precise nature of the motor neuronspecific defect in SMA 1 is not known, the SMN protein has been implicated in several pathways, including nucleo-cytoplasmic transportation, UsnRNP assembly, transcription, and apoptosis (7). SMN can serve as an anti-apoptotic factor in neuronal cells, whereas SMN⌬7 and C-terminal missense mutations promote apoptosis (8). The means by which SMN achieves pro-and anti-apoptotic activities are not known. SMN self-association is a prerequisite for essentially all SMN functions (9 -13). The SMN protein self-associates independently through regions encoded by exons 2b and 6, and the ability to homodimerize correlates with disease severity (14, 15). The primary product of SMN2, SMN⌬7, lacks exon 7, and the resultant protein has a reduced ability to self-associate, accounting for the inability of SMN2 to compensate for the loss of SMN1 (15). The tumor suppressor protein p53 is multifunctional factor involved in cell cycle control (16), DNA repair (17, 18), transcription activation (19,20), and apoptosis (21). p53 can induce apoptosis through several pathways, including mechanisms that are dependent or independent of p53-mediated transcriptional activity (21,22). Under normal physiological conditions, p53 protein levels are maintained at relatively low levels through a negative feedback loop mediated by HDM2 (23-25). ...

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Non-activated p53 co-localizes with sites of transcription within both the nucleoplasm and the nucleolus

Cited by 73 publications

References 42 publications

Energy-dependent nucleolar localization of p53 in vitro requires two discrete regions within the p53 carboxyl terminus

Energy-dependent nucleolar localization of p53 in vitro requires two discrete regions within the p53 carboxyl terminus

Nuclear localization of DEDD leads to caspase-6 activation through its death effector domain and inhibition of RNA polymerase I dependent transcription

A Direct Interaction between the Survival Motor Neuron Protein and p53 and Its Relationship to Spinal Muscular Atrophy

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