Phosphorylation-Dependent Migration of Retinoblastoma Protein into the Nucleolus Triggered by Binding to Nucleophosmin/B23

Takemura, Masaharu; Ohoka, Fumiharu; Perpelescu, Marinela; Ogawa, Masanori; Matsushita, Hidenobu; Takaba, T; Akiyama, Tetsu; Umekawa, Hayato; Furuichi, Yukio; Cook, Peter R.; Yoshida, Shonen

doi:10.1006/excr.2002.5523

Cited by 38 publications

(32 citation statements)

References 41 publications

(43 reference statements)

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“…Hypophosphorylated Rb inhibits cell cycle progression by tightly associating with E2F1 and preventing its transcriptional activity, and Rb phosphorylation releases its inhibitory sequestration on E2F1 (30). Hyperphosphorylated Rb protein is imported into nucleoli late in the S or G 2 phase by binding to B23 (27). Here we also found that B23 robustly binds to Rb, which is regulated by its sumoylation on K263 (Fig.…”

Section: Discussionsupporting

confidence: 67%

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Sumoylation of nucleophosmin/B23 regulates its subcellular localization, mediating cell proliferation and survival

Liu¹,

Liu²,

Jang³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Nucleophosmin/B23 is a major multifunctional nucleolar phosphoprotein that plays a critical role in ribosome biogenesis and cell proliferation. Arf tumor suppressor binds B23 and enhances its sumoylation. However, the biological effects of this event remain unknown. Here we show that B23 is sumoylated on both Lysine 230 and 263 residues, but the latter is the major one. Mutation of K263, but not K230, into R abolishes its centrosomal and nucleolar residency. Moreover, Rb binds to wild-type B23, but fails to interact with K263R. Sumoylation enhances B23 binding to Rb. Consequently, B23 potently stimulates E2F1-mediated transcriptional activity, which is abolished in B23 K263R. Further, K263R mutation makes B23 vulnerable to caspase-3 cleavage and sensitizes cells to apoptosis. Surprisingly, K230R mutant strongly binds to phosphatidylinositol-3,4,5-trisphosphate and suppresses DNA fragmentation. Thus, B23 sumoylation regulates its subcellular localization, cell proliferation, and survival activities.centrosome ͉ nucleolus ͉ sumoylation ͉ K263 N ucleophosmin (NPM)/B23 is a multifunctional protein involved in many cellular activities, and it has been attributed with both oncogenic and tumor-suppressive functions. B23 is more abundant in tumor and growing cells than in normal resting cells (1, 2). In addition, B23 is frequently found in the chromosomal translocation associated with several hematopoietic malignancies, such as acute promyelocytic leukemia (3), anaplastic large-cell lymphomas (4), and myelodysplasia/acute myeloid leukemia (5). Furthermore, certain mutations in the NPM gene incur the cytoplasmic localization of mutated B23, which has been proposed as a biomarker for certain acute myelogenous leukemia (6, 7). Overexpression of B23 induces cell cycle arrest in normal fibroblasts, whereas it promotes S phase entry in cells lacking p53. Conversely, knocking down B23 inhibits the processing of preribosomal RNA and induces cell death (8). In agreement with these observations, overexpression of B23 decreases the susceptibility of human leukemia HL-60 cells to retinoic acid-induced differentiation and apoptosis as well as UV-induced apoptosis in NIH 3T3 cells (9-11). Nonetheless, B23 can be cleaved by active caspase-3, which may influence its antiapoptotic action (12). It has been shown that B23 suppresses hypoxia or UV-induced cell death by repressing p53 phosphorylation and transcription activity (13,14). Recently, we presented biochemical evidence revealing that B23 is a nuclear phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P 3 ] receptor, and this complex directly interacts with caspase-activated DNase and inhibits its DNA fragmentation activity (15). Thus, these findings demonstrate that B23 acts as a physiologically important antiapoptotic protein. However, emerging evidence demonstrates that B23 can also act as a tumor suppressor. Npm germ-line deletion reveals that it is essential for embryonic development and the maintenance of genomic stability. Npm1 heterozygosity accelerates oncogenesis both in ...

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Section: Discussionsupporting

confidence: 67%

“…Hyperphosphorylated retinoblastoma (Rb) protein is imported into nucleoli late in S or G2 phase through binding to B23 (27). To explore whether sumoylation plays any role in mediating the interaction between B23 and Rb, we conducted an in vitro binding assay with recombinant GST-Rb protein.…”

Section: Sumoylation Of B23 Is Required For Its Binding To Retinoblasmentioning

confidence: 99%

Sumoylation of nucleophosmin/B23 regulates its subcellular localization, mediating cell proliferation and survival

Liu¹,

Liu²,

Jang³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…78,81 Phosphorylation of Rb also mediates its nucleolar accumulation at the end of S-phase through an interaction with nucleophosmin. 82 Besides phosphorylation, acetylation may also affect partitioning of nucleolar proteins between the nucleolus and the nucleoplasm. For example, the DNA damage-dependent redistribution of WRN from nucleoli to RPA-containing repair foci is significantly enhanced by the deacetylase inhibitor trichostatin A.…”

Section: The "Plurifunctional" Nucleolus and Tumor Suppressionmentioning

confidence: 99%

Beyond Repair Foci: Subnuclear Domains and the Cellular Response to DNA Damage

Dellaire¹,

Bazett-Jones²

2007

Cell Cycle

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“…Akt nuclear translocation was blocked by pretreatment for 1 h with 25 mM Ly294002. We used an antibody to the resident nucleolar protein B23/nucleophosmin (Takemura et al, 2002) to equalize loading.…”

Section: Ngf Treatment Induces Nuclear Translocation Of An Active Aktmentioning

confidence: 99%

Threonine 308 phosphorylated form of akt translocates to the nucleus of PC12 cells under nerve growth factor stimulation and associates with the nuclear matrix protein nucleolin

Borgatti

Martelli

Tabellini³

et al. 2003

Journal Cellular Physiology

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We have examined the issue of whether or not in PC12 cells it may be observed a nerve growth factor (NGF) nuclear translocation of an active (phosphorylated) Akt. Western blot analysis with antibodies to either total or phosphorylated Akt showed a maximal nuclear translocation after 15 min of NGF stimulation. NGF increased rapidly and transiently the enzymatic activity of immunoprecipitable nuclear Akt and after 45 min the values returned to a level close to the basal one. Enzyme translocation was blocked by the selective phosphoinositide 3-kinase inhibitor, LY294002. Confocal microscopy of samples stained with antibody to Akt showed an evident increase in immunostaining intensity in the nuclear interior after NGF treatment. Treatment of cells with inhibitors of protein phosphatase PP2A, calyculin A, or okadaic acid, maintained the phosphorylation levels of nuclear Akt. Immunoprecipitation experiments revealed an association between Akt and PP2A that was maximal when nuclear Akt activity was decreased. Both total and active Akt associated with the nuclear matrix and, in particular, with the protein nucleolin, with which Akt co-immunoprecipitated. These findings strongly suggest that the intranuclear translocation of active Akt is an important step in the signaling pathways elicited by the neurotrophin NGF and that the intranuclear control of Akt is achieved through the action of PP2A.

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Phosphorylation-Dependent Migration of Retinoblastoma Protein into the Nucleolus Triggered by Binding to Nucleophosmin/B23

Cited by 38 publications

References 41 publications

Sumoylation of nucleophosmin/B23 regulates its subcellular localization, mediating cell proliferation and survival

Sumoylation of nucleophosmin/B23 regulates its subcellular localization, mediating cell proliferation and survival

Beyond Repair Foci: Subnuclear Domains and the Cellular Response to DNA Damage

Threonine 308 phosphorylated form of akt translocates to the nucleus of PC12 cells under nerve growth factor stimulation and associates with the nuclear matrix protein nucleolin

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