Over-expression of nucleophosmin/B23 decreases the susceptibility of human leukemia HL-60 cells to retinoic acid-induced differentiation and apoptosis

Hsu, Chen Y.; Yung, Benjamin Yat‐Ming

doi:10.1002/1097-0215(20001101)88:3<392::aid-ijc11>3.0.co;2-7

Cited by 53 publications

(48 citation statements)

References 31 publications

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“…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)(10)(11). Nonetheless, B23 can be cleaved by active caspase-3, which may influence its antiapoptotic action (12).…”

supporting

confidence: 61%

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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supporting

confidence: 61%

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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“…For example, B23-RAR fusion proteins originated from acute promyelocytic leukemia cells can interact with co-repressors and co-activators, resulting in both transcriptional repression and activation (50). Similarly, B23 can both repress IRF1 (interferon regulatory factor 1)-mediated transcriptional activation (18,19) and relieve YY1-induced transcriptional repression by direct interaction with YY1 transcription factor (20). Interestingly, a recent study shows that B23 works as an AP2␣-binding transcriptional corepressor by remodeling local chromatin structure (51).…”

Section: Discussionmentioning

confidence: 99%

“…It has also been established that B23 can function as an acidic histone chaperone that helps assemble nucleosomes in vitro (17). B23 can either repress (18,19) …”

mentioning

confidence: 99%

“…It has also been established that B23 can function as an acidic histone chaperone that helps assemble nucleosomes in vitro (17). B23 can either repress (18,19) or stimulate transcription (20,21), depending on the promoter context and/or inter-acting transcription factors. There are controversial reports concerning the role of B23 in the regulation of tumor suppressor p53 stability and transcription.…”

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confidence: 99%

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Nucleophosmin/B23 Negatively Regulates GCN5-dependent Histone Acetylation and Transactivation

Zou

Giannone

et al. 2008

Journal of Biological Chemistry

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Nucleophosmin/B23 is a multifunctional phosphoprotein that is overexpressed in cancer cells and has been shown to be involved in both positive and negative regulation of transcription. In this study, we first identified GCN5 acetyltransferase as a B23-interacting protein by mass spectrometry, which was then confirmed by in vivo co-immunoprecipitation. An in vitro assay demonstrated that B23 bound the PCAF-N domain of GCN5 and inhibited GCN5-mediated acetylation of both free and mononucleosomal histones, probably through interfering with GCN5 and masking histones from being acetylated. Mitotic B23 exhibited higher inhibitory activity on GCN5-mediated histone acetylation than interphase B23. Immunodepletion experiments of mitotic extracts revealed that phosphorylation of B23 at Thr 199 enhanced the inhibition of GCN5-mediated histone acetylation. Moreover, luciferase reporter and microarray analyses suggested that B23 attenuated GCN5-mediated transactivation in vivo. Taken together, our studies suggest a molecular mechanism of B23 in the mitotic inhibition of GCN5-mediated histone acetylation and transactivation.The acetylation of nucleosomal histones by histone acetyltransferases (HATs) 5 has been known for several decades. Histone-modifying enzymes, such as GCN5 (general control of amino acid synthesis 5) in the Spt-Ada-Gcn5 acetyltransferase (SAGA) and Esa1p in the NuA4 complex, can acetylate specific lysine residues in histone N-terminal tails (1). According to the histone code hypothesis (2), site-specific acetylation of histone tails may trigger chromatin remodeling that leads to retention of effector proteins to active promoters and formation of transcriptionally active chromatin regions.GCN5 was originally identified as a transcriptional coactivator in yeast and was proposed to contribute to transcription by establishing interactions between certain activators and transcriptional complexes (3). GCN5 enhances transcription through its intrinsic acetyltransferase activity (4), which facilitates acetylation of histones and nonhistone substrates (3). Recruitment of the SAGA complex greatly increases transcriptional activation in vitro (5), and the requirement of GCN5 for chromatin remodeling has been demonstrated in vivo (6). However, the mechanism(s) that regulates GCN5 activity particularly in the context of histone acetylation has yet to be examined in detail. Potentially, GCN5 HAT activity can be regulated through posttranslational modifications, interacting with other proteins or at the level of substrate modifications. For example, phosphorylation by the Ku-DNA-dependent protein kinase or sumoylation may regulate GCN5-HAT activity (7,8). Also, interaction with the SANT domain of the Ada2 affects GCN5-HAT activity in yeast (9). Likewise, modification of substrates, such as phosphorylation of H3 serine 10, increases GCN5 acetylation activity toward lysine 14 of H3 (10, 11).Nucleophosmin/B23, also known as NPM1, NO38, or numatrin, has been identified as a phosphoprotein that possesses multiple cellular func...

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“…Overexpression or downregulation of NPM reportedly alters the cellular status with respect to proliferation, differentiation and apoptosis, although some contradictory results have been reported. (17,18) NPM function appears to be different depending on whether or not wild-type p53 is present. (12,19) It has been reported that NPM has an important role in the cell cycle.…”

Section: Expression and Function Of Npmmentioning

confidence: 99%

Nucleophosmin: A versatile molecule associated with hematological malignancies

Naoe

Suzuki

Kiyoi³

et al. 2006

Cancer Science

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Nucleophosmin (NPM) is a nucleolar phosphoprotein that plays multiple roles in ribosome assembly and transport, cytoplasmicnuclear trafficking, centrosome duplication and regulation of p53. In hematological malignancies, the NPM1 gene is frequently involved in chromosomal translocation, mutation and deletion. The NPM1 gene on 5q35 is translocated with the anaplastic lymphoma kinase (ALK) gene in anaplastic large cell lymphoma with t(2;5). The MLF1 and RARA genes are fused with NPM1 in myelodysplastic syndrome and acute myeloid leukemia (AML) with t(3;5) and acute promyelocytic leukemia with t(5;17), respectively. In each fused protein, the Nterminal NPM portion is associated with oligomerization of a partner protein leading to altered signal transduction or transcription. Recently, mutations of exon 12 have been found in a significant proportion of de novo AML, especially in those with a normal karyotype. Mutant NPM is localized aberrantly in the cytoplasm, but the molecular mechanisms for leukemia remain to be studied. N ucleophosmin (NPM), also called B23, numatrin or NO38, was isolated as an abundant nucleolar phosphoprotein, whose expression level is increased significantly by several kinds of stimulation and transformation. (1,2) In 1989, a human NPM cDNA encoding a 294-amino-acid protein was cloned. (3) In 2002, a shorter isoform encoding a 259-amino acid protein that differs at the C-terminus was also isolated. (4) The NPM1 gene spans 25 kb, contains 12 exons and maps to chromosome 5q35. (4,5) Exon 8 is frequently skipped, and exon 10 is used only for the short isoform. Although the biological significance of the short isoform remains unclear, its expression is increased in radiation-insensitive cell lines and the product is localized in the cytoplasm as well as in the nucleus. (4,6) The structural features of NPM consist of an oligomerization domain, a metalbinding motif, a bipartite nuclear localization signal, two Asp/ Glu-rich domains, phosphorylation sites for CDK2 and a nucleor localization signal. (6,7) NPM1 has been recognized by oncologists as a partner gene for various chromosomal translocations: NPM-anaplastic lymphoma kinase (ALK) in anaplastic large cell lymphoma (ALCL) with t(3;5), NPM-RARA in acute promyelocytic leukemia (APL) with t(5;17), and NPM-MLF1 in acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS) with t(3;5). (8)(9)(10) (Fig. 1, 2) In each chimeric gene product, the N-terminal NPM portion is thought to act as the interface for oligomerization and oncogenic conversion of the C-terminal functional domain such as a kinase or transcription factor. Recently, NPM was associated with centrosome duplication and the regulation of p53, (11,12) and might have a role as a tumor suppressor. Expression and function of NPMNucleophosmin is an abundant and ubiquitously expressed phosphoprotein. It is located mainly in the nucleolus and shuttles between the nucleus and cytoplasm. (13,14) NPM has been proposed to be associated with the synthesis and processing of ribosomal RNA (rRNA), regu...

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Over-expression of nucleophosmin/B23 decreases the susceptibility of human leukemia HL-60 cells to retinoic acid-induced differentiation and apoptosis

Cited by 53 publications

References 31 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

Nucleophosmin/B23 Negatively Regulates GCN5-dependent Histone Acetylation and Transactivation

Nucleophosmin: A versatile molecule associated with hematological malignancies

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