Identification and Characterization of a Leukocyte-specific Component of the Nuclear Body

Bloch, Donald B.; Monte, Suzanne M. de la; Guigaouri, Pavel; Filippov, Alexander K.; Bloch, Kenneth D.

doi:10.1074/jbc.271.46.29198

Cited by 94 publications

(77 citation statements)

References 52 publications

(41 reference statements)

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“…Since Sp140/ LYSp100B is only expressed in lymphocytes, it has been postulated that LANDs function is a tissue-restricted manner. Expression of Sp140 is enhanced at mRNA and protein levels by IFNg (Bloch et al, 1996(Bloch et al, , 1999. However, Sp140 is associated with a subset of PMLSp100 NBs in IFNg-treated cells (Bloch et al, 1999).…”

Section: Sp140mentioning

confidence: 94%

“…The carboxyl portion of Sp140 contains a plant homeobox domain and bromodomain; it is 39% identical to the carboxyl portion of murine nuclear hormone receptor transcription intermediary factor 1a (TIF1a). Sp140 is localized on the PML NBs in di erentiated HL60 and NB4 cells (Bloch et al, 1996) and in resting cells (Bloch et al, 1999). However, it was reported that Sp140/LYSp100B, for LYSp100-associated nuclear dots (LANDs), appear to be distinct in location and morphology from PML NBs in Blymphocytic cell lines (Dent et al, 1996).…”

Section: Sp140mentioning

confidence: 99%

“…Serum from a patient with primary biliary cirrhosis was used to identify a cDNA encoding a novel component of the NBs, a 140 kDa protein designated Sp140 (Bloch et al, 1996). The amino-terminal portion of Sp140 is 49% identical to the amino-terminal region of Sp100.…”

Section: Sp140mentioning

confidence: 99%

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Role and fate of PML nuclear bodies in response to interferon and viral infections

2001

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Interferons (IFNs) are a family of secreted proteins with antiviral, antiproliferative and immunomodulatory activities. The di erent biological actions of IFN are believed to be mediated by the products of speci®cally induced cellular genes in the target cells. The promyelocytic leukaemia (PML) protein localizes both in the nucleoplasm and in matrix-associated multi-protein complexes known as nuclear bodies (NBs). PML is essential for the proper formation and the integrity of the NBs. Modi®cation of PML by the Small Ubiquitin MOdi®er (SUMO) was shown to be required for its localization in NBs. The number and the intensity of PML NBs increase in response to interferon (IFN). Inactivation of the IFN-induced PML gene by its fusion to retinoic acid receptor alpha alters the normal localization of PML from the punctuate nuclear patterns of NBs to microdispersed tiny dots and results in uncontrolled growth in Acute Promyelocytic Leukaemia. The NBs-associated proteins, PML, Sp100, Sp140, Sp110, ISG20 and PA28 are induced by IFN suggesting that nuclear bodies could play a role in IFN response. Although the function of PML NBs is still unclear, some results indicate that they may represent preferential targets for viral infections and that PML could play a role in the mechanism of the antiviral action of IFNs. Viruses, which require the cellular machinery for their replication, have evolved di erent ways to counteract the action of IFN by inhibiting IFN signalling, by blocking the activities of speci®c antiviral mediators or by altering PML expression and/or localization on nuclear bodies. Oncogene (2001) 20, 7274 ± 7286.

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Section: Sp140mentioning

confidence: 94%

Section: Sp140mentioning

confidence: 99%

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Role and fate of PML nuclear bodies in response to interferon and viral infections

2001

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“…28), Williams syndrome transcription factor (WSTF) in the chromatin-remodeling complex WINAC 29 , and the TIF1 family proteins (α, β, γ and δ; note that TIF1β is also known as KAP1 or TRIM28) 30 . This tandem PHD finger-bromodomain is also found in Sp140, a leukocytespecific protein in the nuclear body that is involved in the pathogenesis of acute promyelocytic leukemia and viral infection 31 . Mutations of PHD fingers, particularly those that disrupt zinc coordination, have been linked to tumor formation and genetic disorders 32 .…”

mentioning

confidence: 95%

Structural insights into human KAP1 PHD finger–bromodomain and its role in gene silencing

Zeng

Yap

Ivanov

et al. 2008

Nat Struct Mol Biol

118

117

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The tandem PHD finger-bromodomain, found in many chromatin-associated proteins, has an important role in gene silencing by the human co-repressor KRAB-associated protein 1 (KAP1). Here we report the three-dimensional solution structure of the tandem PHD finger-bromodomain of KAP1. The structure reveals a distinct scaffold unifying the two protein modules, in which the first helix, α Z , of an atypical bromodomain forms the central hydrophobic core that anchors the other three helices of the bromodomain on one side and the zinc binding PHD finger on the other. A comprehensive mutation-based structure-function analysis correlating transcriptional repression, ubiquitin-conjugating enzyme 9 (UBC9) binding and SUMOylation shows that the PHD finger and the bromodomain of KAP1 cooperate as one functional unit to facilitate lysine SUMOylation, which is required for KAP1 co-repressor activity in gene silencing. These results demonstrate a previously unknown unified function for the tandem PHD finger-bromodomain as an intramolecular small ubiquitin-like modifier (SUMO) E3 ligase for transcriptional silencing.Chemical modifications of chromatin on the DNA (for example, methylation of cytosine) and DNA-packing histones (for example, acetylation, methylation, phosphorylation, ubiquitination and SUMOylation) are important in the epigenetic control of gene transcription in response to physiological and environmental stimuli [1][2][3] . An emerging model suggests that there is an 'epigenetic code' embedded within chromatin to signify regions of distinct nuclear activities, such as heterochromatin formation or transcriptional activation [4][5][6] . It is thought that the epigenetic code is established by chromatin-modifying enzymes and interpreted by proteins that bind the chromatin in a modification-sensitive manner. The discovery of methyl-CpG binding domains 7 , bromodomains as acetyllysine binding The tandem bromodomain-PHD finger of the human transcriptional coactivator p300/CBP has been shown to be interdependent in interactions with nucleosomes 27 . A more common, reversely connected motif, the PHD finger-bromodomain, is found in many chromatinassociated proteins including histone lysine methyl-transferase MLL1 (ref. 28), Williams syndrome transcription factor (WSTF) in the chromatin-remodeling complex WINAC 29 , and the TIF1 family proteins (α, β, γ and δ; note that TIF1β is also known as KAP1 or TRIM28) 30 . This tandem PHD finger-bromodomain is also found in Sp140, a leukocytespecific protein in the nuclear body that is involved in the pathogenesis of acute promyelocytic leukemia and viral infection 31 . Mutations of PHD fingers, particularly those that disrupt zinc coordination, have been linked to tumor formation and genetic disorders 32 .More recently, it has been reported that the PHD finger of the human co-repressor KAP1 functions as a unique SUMO E3 ligase that is required for KAP1's gene transcription repression activity 33 .To understand its molecular function in gene silencing, we solved the three-dim...

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“…167 These macromolecular protein-rich complexes are tightly bound to the nuclear matrix 155,163,164 and are known to contain several other proteins, including Sp100, NDP52, PIC1/SUMO-1, and Int-6. 165,[168][169][170][171][172][173][174] Progressive accretion of proteins gives rise to a characteristic ringlike appearance, 154,156,162 especially in cells overexpressing PML.…”

Section: The (15;17) Translocation and Its Variantsmentioning

confidence: 99%

Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry

Falini

Mason

2002

Blood

176

147

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IntroductionTranslocations, deletions, and other nonrandom chromosomal abnormalities 1,2 play a central role in the pathogenesis of many human hematologic malignant diseases. A growing number of studies are revealing the ways in which these chromosomal alterations affect specific genes, such as those encoding nuclear transcription factors. However, any gene implicated in the neoplastic process can act only through the protein it encodes. Many of the consequences of chromosomal changes with respect to abnormal protein expression have been inferred indirectly by analysis of messenger RNA (mRNA) transcription, but it is clear that protein and mRNA levels do not always correlate. For example, germinalcenter B cells appear to contain BCL-2 message but little protein, 3,4 and the same is true for TAL-1 in erythroid cells. 5 Many examples of the opposite combination (high protein and little or no message) also exist, such as BCL-2 in mature lymphocytes 6,7 and elastase in mature myeloid cells. 8 Antibody-based detection of the protein is therefore required, but this frequently cannot be done because of a lack of suitable reagents. Consequently, we are often ignorant not only about patterns of expression of oncogenic proteins in hematologic neoplasms but also about possible abnormalities in the distribution and subcellular localization of these proteins.Most of the currently recognized genetic alterations in human leukemias and lymphomas result in either activation of a quiescent gene or creation of a hybrid gene encoding a chimeric protein. Table 1 summarizes the genetic abnormalities that have been studied using antibodies specific for the protein products of genes involved in such rearrangements. We here review the immunocytochemical studies that have been done with these antibodies and assess, for each protein, whether abnormalities demonstrable by immunocytochemistry are of clinical value in determining diagnosis or predicting prognosis. Immunocytochemical findings that are of value are discussed below, whereas those for which no clear clinical applications have been observed are described briefly in Table 2. Genes activated by chromosomal changesThe CCND1 (BCL-1) gene and its protein product (cyclin D1) CCND1 (BCL-1) gene. The (11;14)(q13;q32) translocation, 9 an anomaly often found in mantle cell (centrocytic) lymphoma 10,11 and occasionally in other B-cell neoplasms, notably myeloma, 12,13 From For personal use only. on May 12, 2018. by guest www.bloodjournal.org From juxtaposes the CCND1 (BCL-1) locus encoding cyclin D1 on chromosome 11 to an immunoglobulin-enhancer sequence on chromosome 14. 9 The CCND1 gene is transcriptionally silent in normal lymphohemopoietic tissues 14,15 ; thus, expression of the protein may promote neoplastic cell proliferation by perpetuating the transition from G 1 to S. 16 Antibodies to cyclin D1. Several antibodies recognizing cyclin D1 have been described (Table 3), [14][15][16][17][18] but hematopathologists know that immunocytochemical detection of cyclin D1 in routinely processe...

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Identification and Characterization of a Leukocyte-specific Component of the Nuclear Body

Cited by 94 publications

References 52 publications

Role and fate of PML nuclear bodies in response to interferon and viral infections

Role and fate of PML nuclear bodies in response to interferon and viral infections

Structural insights into human KAP1 PHD finger–bromodomain and its role in gene silencing

Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry

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